Standard TMS works for many people. But its antidepressant effect depends on a specific biological process — and for some patients, that process doesn’t engage fully. DCS-augmented TMS is designed to change that.
By adding D-cycloserine (DCS), a medication that amplifies the brain’s plasticity response to magnetic stimulation, we can make TMS more effective for patients who had a partial response before, or who want to maximize their chances of full remission from the start.
This is the highest-specificity combination protocol we offer. Here is the science behind it, the evidence supporting it, and what it means for you as a patient.
To understand why DCS augmentation makes sense, you need to understand what TMS is actually doing to the brain.
The antidepressant effects of TMS are thought to depend on synaptic plasticity — specifically, a process called long-term potentiation (LTP). Every session of TMS delivers magnetic pulses to the prefrontal cortex. The goal is not just to stimulate — it is to drive lasting change in how those neurons connect and communicate.
LTP is gated by NMDA receptors: the molecular switches that determine whether the brain’s response to stimulation becomes a lasting change or simply fades. The theta-burst stimulation protocol — the form of TMS most commonly used today — has been shown in multiple studies to be NMDA-receptor dependent. When NMDA receptors are functioning well, TMS drives robust plasticity. When they are underactive, TMS stimulates the brain, but the lasting circuit changes don’t always fully take hold.
D-cycloserine directly addresses this problem.
D-cycloserine (DCS) is a medication originally developed as an antibiotic for tuberculosis. It was subsequently identified as a partial agonist of NMDA receptors — meaning it amplifies NMDA receptor activity without fully activating it.
In the context of TMS, DCS is taken approximately 30 minutes before each session. This timing is deliberate: by amplifying NMDA receptor activity during the stimulation itself, DCS lowers the threshold for long-term potentiation, allowing TMS to drive stronger and more lasting changes in the targeted circuits.
At Interventional Psychiatry of Philadelphia, the DCS dose is taken on-site, under clinical supervision, before each TMS session.
The pivotal trial supporting DCS-augmented TMS was published in JAMA Psychiatry in 2022 by Cole, Sohn, Harris, Bray, Patten, and McGirr at the University of Calgary.
The trial was a double-blind, placebo-controlled randomized clinical study involving 50 participants with major depressive disorder. All participants received intermittent theta-burst stimulation (iTBS) — 20 sessions targeting the left dorsolateral prefrontal cortex. Half received D-cycloserine (100 mg) approximately 30 minutes before each session; half received a placebo.
The results were striking. DCS-augmented TMS produced a response rate of 74% and a remission rate of 39%. The TMS-plus-placebo group produced a response rate of 29% and a remission rate of 4%. DCS more than doubled both response and remission rates, with a large effect size of 0.99.
To put that in plain terms: in this trial, standard TMS produced a meaningful response in roughly 29% of patients. Adding DCS raised that to 74%. The remission rate went from 4% to 39%. That is not a marginal improvement. It is a substantial shift in the clinical odds.
It is important to note that this was a single 50-patient trial conducted at one center, and replication in a larger multisite study is still needed. The Cole et al. findings are the strongest controlled evidence available for this approach — they are encouraging and warrant serious clinical attention, while the broader evidence base continues to develop.
A 2025 case report published in a peer-reviewed journal documented a 28-year-old woman who did not respond to an initial course of rTMS, experienced clinical worsening including suicidal ideation and hospitalization, and then achieved rapid remission of suicidal thoughts and marked improvement in depression following a second course of rTMS augmented with DCS. The DCS used was the standard FDA-approved 250 mg dose — not a research-compounded formulation — making this the first published real-world report using a readily obtainable DCS formulation. A single case is not clinical evidence, but it is meaningful for patients who have not responded to TMS and are considering whether augmentation is worth exploring.
The plasticity mechanism targeted by DCS is not limited to depression. A 2025 randomized, sham- and placebo-controlled trial published in the American Journal of Psychiatry (McGirr et al., University of Calgary) tested DCS-augmented iTBS specifically for OCD. The trial was stopped early due to the manufacturer discontinuing the DCS product mid-study, limiting the final sample size. Despite that, the DCS and iTBS group showed approximately 39% improvement in OCD symptom scores (measured by the YBOCS) compared to approximately 17% improvement in the iTBS-alone group — a meaningful difference even in a truncated dataset.
For patients who have OCD alongside depression — a common co-occurring presentation — DCS-augmented TMS may offer benefit on both fronts. The research group has described this as a potentially transdiagnostic mechanism: the same neuroplasticity pathway that mediates antidepressant response appears to mediate OCD response as well.
Research on DCS augmentation is extending into accelerated TMS protocols. A 2025 double-blind, placebo-controlled trial from McLean Hospital (Brown, Ganesh, Kweon, and McGirr) examined whether DCS could enhance single-day accelerated iTBS in patients with major depressive disorder. The McLean team noted that DCS enhances TMS-induced corticomotor plasticity and has produced large clinical efficacy improvements in conventional daily TMS — and sought to determine whether the same holds for accelerated protocols.
The ONE-D case series (Vaughn, Marino, Downar et al., University of Toronto, 2025) provides related context: this single-day TMS protocol uses both DCS and lisdexamfetamine as neuroplasticity enhancers delivered before a full 20-session course completed in one day. The case series of 32 treatment-resistant depression patients reported an 87.5% response rate and 71.9% remission rate at six weeks. At 26 weeks, 50% maintained sustained remission. This is not yet an RCT, and the contributions of DCS versus the overall protocol cannot be fully separated — but the results are among the highest published for any TMS protocol.
If you are considering accelerated TMS, DCS augmentation may be an additional layer of protocol enhancement worth discussing with your clinician.
DCS-augmented TMS follows the same structure as a standard TMS course. Approximately 30 minutes before each session, you take a dose of D-cycloserine on-site under clinical supervision. This allows precise timing coordination and clinical monitoring throughout the course.
The TMS session itself — theta-burst stimulation to the left dorsolateral prefrontal cortex — proceeds as it would for a standard course. No additional equipment is needed beyond what is used for standard TMS.
D-cycloserine (DCS) is a medication originally developed as an antibiotic for tuberculosis. In the context of TMS augmentation, it functions as a partial agonist of NMDA receptors — amplifying the brain’s plasticity response to magnetic stimulation without overstimulating those receptors. When taken approximately 30 minutes before a TMS session, it strengthens the long-term potentiation that TMS is designed to drive. The 2022 Cole et al. trial used a 100 mg dose; a 2025 real-world case report used the standard 250 mg FDA-approved formulation.
TMS works by driving synaptic plasticity — specifically, long-term potentiation — in the prefrontal cortex. That process is gated by NMDA receptors. In some patients with depression, NMDA receptor activity is blunted, meaning TMS stimulates the brain but the lasting circuit changes don’t fully occur. DCS partially activates those receptors before each session, lowering the threshold for LTP and allowing TMS to produce more substantial and lasting changes. In the 2022 Cole et al. JAMA Psychiatry trial, this approach more than doubled response rates (74% vs. 29%) and remission rates (39% vs. 4%) compared to TMS with placebo.
Yes. DCS-augmented TMS is available at Interventional Psychiatry of Philadelphia, located at 2401 Pennsylvania Ave, Suite 1C44-45, Philadelphia, PA 19130. The D-cycloserine dose is taken on-site, approximately 30 minutes before each session, under clinical supervision.
Research published in the American Journal of Psychiatry in 2025 (McGirr et al.) found that combining TMS with D-cycloserine improved OCD symptoms by approximately 39% compared to 17% with TMS alone, in a randomized controlled trial. If you have OCD, or OCD alongside depression, DCS augmentation is worth discussing with your treating clinician.
Patients who had a partial response to a prior TMS course are strong candidates — the mechanism suggests that full LTP may not have occurred, and DCS augmentation addresses that directly. Patients beginning TMS for the first time with moderate-to-severe treatment-resistant depression may also benefit, given the significantly higher response rates in the Cole et al. trial. This is a clinical determination made through consultation.
DCS at the doses used in TMS augmentation was well-tolerated in the Cole et al. 2022 trial, with mild side effects in a small number of participants comparable to the placebo group. As with any medication, individual responses vary and side effects should be discussed with your clinician before beginning.
Research is ongoing. The McLean Hospital 2025 trial (Brown et al.) examined this question directly in a double-blind, placebo-controlled study. The ONE-D protocol from the University of Toronto incorporates DCS as part of a single-day accelerated course. Whether the combination is appropriate for you is a clinical determination — raise it with your clinician if you are considering an accelerated protocol.
The D-cycloserine dose is taken on-site, approximately 30 minutes before each TMS session, under clinical supervision. This allows precise timing coordination and monitoring throughout the course.
If you’ve had a partial TMS response — or if you want to maximize your chances of full remission from the start — DCS augmentation is the most clinically specific protocol we offer.
Call 215-222-0310 or request a consultation online. We are located at 2401 Pennsylvania Ave, Suite 1C44-45, Philadelphia, PA 19130, serving patients throughout Philadelphia and the Delaware Valley.
