Combining TMS With Medication: Augmentation Research

Most people who have TMS are taking psychiatric medication during the course, and continuing a stable antidepressant is a reasonable default. The evidence on whether the combination beats TMS alone is mixed: a large trial that started TMS and a new antidepressant together found no added benefit, while a meta-analysis of trials in treatment-resistant depression found that adding active TMS to medication clearly outperformed adding sham.

Using a drug specifically to boost TMS is a different matter. D-cycloserine and stimulants have been studied as enhancers, with one promising small trial and some negative or uncontrolled data. That use is off-label and research-stage, and it is not part of any FDA-cleared TMS protocol. Benzodiazepines, on the other hand, have repeatedly been linked to weaker or slower response in observational studies.

What the FDA labels and trials assumed

The original 2011 FDA classification describes TMS for patients "currently not on any antidepressant therapy." That is legacy wording; later labels are broader, and the adolescent clearances from 2024 onward are explicitly "as an adjunct," meaning alongside antidepressants. The NeuroStar adult label describes people who have not improved enough with prior antidepressant medication in the current episode; its indication wording does not mention stopping medication.

The key trials handled medication in different ways, which is one reason results vary:

So TMS has shown efficacy both with and without medication. The question is not whether combining is allowed, but whether it adds anything.

Does TMS plus an antidepressant work better?

Starting both at once: no clear benefit

In a 2007 multicenter trial, 127 patients with moderate to severe depression were randomized to real or sham rTMS for 3 weeks while starting a new antidepressant at the same time. Response was 31% in both groups. APA's 2010 guideline cited a large sham-controlled trial of TMS added to medication that "showed no significant benefit." Starting two treatments together does not appear to speed or strengthen the response, at least with the protocols of that era.

Adding TMS after medication has failed: benefit

The more common situation is different: someone is already on an antidepressant that has not worked well enough. A 2014 meta-analysis pooled seven double-blind, sham-controlled trials of rTMS added to antidepressants in treatment-resistant depression, with 279 patients. Active rTMS outperformed sham, with an odds ratio for response of 5.12 and a number needed to treat of 3.4. The trials were small, but the direction supports TMS as an add-on to ongoing medication.

After the course: combination for relapse prevention

In a Chinese randomized trial of 281 people already in remission on antidepressants, relapse over 12 months was 15.9% with monthly clustered rTMS plus antidepressant, 24.2% with rTMS alone and 44.4% with antidepressant alone. Those participants were medication responders rather than TMS responders, so the finding does not transfer directly, but it is consistent with combined treatment being protective. More on this is in how long TMS results last.

Drugs studied to enhance TMS

D-cycloserine

The idea is that TMS, and theta-burst stimulation in particular, works through NMDA-receptor-dependent plasticity, so a drug that boosts NMDA signaling might amplify it. In a single-site, double-blind trial of 50 adults, iTBS plus D-cycloserine 100 mg for the first two weeks produced greater improvement than iTBS plus placebo, with response of 73.9% vs 29.3% and remission of 39.1% vs 4.2%. The authors called it promising but requiring further investigation.

The picture is not uniformly positive. A placebo-controlled single-day study of 30 people, available only as a preprint, gave D-cycloserine 250 mg the night before 10 iTBS sessions and found no difference between groups. The ONE-D single-day protocol combines D-cycloserine and lisdexamfetamine, both off-label, with 20 iTBS sessions; its evidence is a retrospective case series without a placebo group. The Clinical TMS Society states that ONE-D is not FDA-cleared and that its evidence does not meet the threshold to recommend it over better-studied approaches. The details are in one-day accelerated TMS.

Stimulants

In a 2019 study of 181 patients treated with standard rTMS, those taking prescribed psychostimulants had higher week-6 response than those who were not (39.2% vs 22.0%). That was an observational association, uncorrected for multiple comparisons, and the authors said it should be replicated before it changes practice. It was not a controlled test of adding a stimulant to TMS. Recreational stimulants are a separate issue: IFCN lists cocaine and MDMA among factors that lower seizure threshold.

Benzodiazepines

Benzodiazepines (such as lorazepam or clonazepam) are the medication class most consistently linked to poorer TMS response:

• In the 2019 study above, week-6 response was 16.4% in benzodiazepine users vs 35.5% in non-users.
• A 2026 analysis of 388 THREE-D trial participants found benzodiazepine use associated with membership in a minimal-response group.
• A 2025 late-life depression analysis found benzodiazepine use associated with lower odds of a steadily improving trajectory.

All three are observational. People who need benzodiazepines often have more severe anxiety or insomnia, which may itself predict a harder course. None of these studies tested whether tapering a benzodiazepine before TMS improves outcomes. Because stopping a benzodiazepine abruptly can cause serious withdrawal, any reduction is planned gradually with the prescriber and is weighed against the reasons it was started. Why these signals matter for expectations is covered in who responds to TMS.

Medications and seizure risk

FDA's 2011 guidance asks device labeling to call for close monitoring of patients on "tricyclic antidepressants, neuroleptic medications, or other drugs that are known to lower the seizure threshold." The 2021 IFCN safety guideline says the low observed seizure rate no longer supports special caution with such medications, but still recommends documenting them along with other threshold-lowering factors. IFCN also notes that most rTMS patients take CNS-active medications and the observed seizure rate is extremely low. The full numbers are in TMS safety and seizure risk.

Medication changes during a course matter for a practical reason too. Treatment intensity is set from the motor threshold, and anything that shifts brain excitability can make that measurement less accurate; see motor threshold and dosing.

Questions worth settling before a course starts

A short medication review before the first session prevents most of the problems described above. The questions usually covered are:

• Which antidepressant, at what dose, and for how long? A medication that has been at a stable dose for several weeks is easier to keep steady through the course than one that was just changed.
• Is anything due to change soon, such as a planned taper, a new prescription from another doctor, or a dose adjustment for side effects? Timing those changes before or after the course keeps the picture clear.
• Are there sedatives, sleep aids or benzodiazepines, including ones taken only occasionally? These are worth discussing because of the response data, not because they rule TMS out.
• What about alcohol, cannabis and over-the-counter products? Heavy drinking and alcohol withdrawal are named seizure risk factors. Supplements can also interact with prescribed medication.
• Who is the single point of contact? If a primary care doctor, therapist and psychiatrist are all involved, one person should coordinate medication decisions during the course.

An integrative review can also look at factors outside the medication list, such as sleep, thyroid function or nutritional deficiencies, that may be holding back response to any treatment; the approach is described in integrative psychopharmacology.

What standard practice looks like

1. Continue a stable antidepressant unless there is a clear reason to change it. This matches how many trials and real-world cohorts were run.
2. Avoid starting, stopping or changing doses during the course where possible, so changes in mood can be attributed and the motor threshold stays reliable.
3. Review benzodiazepines, sleep medications and any threshold-lowering drugs before the first session, and document all medications, as IFCN recommends.
4. Treat enhancer drugs such as D-cycloserine as research. They are off-label for this purpose and not part of any FDA-cleared protocol.
5. Plan the post-course medication strategy in advance, since there is no single recommended maintenance approach.

These decisions belong in ongoing medication management with your psychiatrist. A patient-friendly version of the day-to-day questions is on Mind Body Seven: medications during TMS.

The TMS therapy page has the practice's current TMS information, and the TMS guide collects the related evidence.

Frequently asked questions

Do I have to stop my antidepressant to have TMS?

Usually not. Many trials and clinics continue a stable antidepressant, and newer FDA-cleared adolescent labels describe TMS as an adjunct to medication. Your psychiatrist will decide based on your situation.

Should I stop my benzodiazepine before TMS?

Not on your own. Observational studies link benzodiazepine use to weaker response, but those studies did not test whether stopping helps, and abrupt discontinuation can be dangerous. Any taper should be planned with your prescriber.

Is D-cycloserine approved to boost TMS?

No. One 50-person trial found a large benefit when it was added to iTBS, but a single-day placebo-controlled study did not, and it is not part of any FDA-cleared TMS protocol. Its use for this purpose is off-label.

Can I start a new antidepressant at the same time as TMS?

It is possible, but it makes it hard to tell which treatment helped, and a large trial that started both together found no added benefit. Most psychiatrists prefer to keep medications stable during the course.

Do ADHD stimulants interfere with TMS?

The one observational study cited here did not find that prescribed stimulants reduce TMS response; it found higher response in people taking them, a result that has not been confirmed in a controlled trial here. Recreational stimulants such as cocaine are a different matter because they lower seizure threshold.

Sources

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3. Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 2022. pmc.ncbi.nlm.nih.gov
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6. Trajectories of response to bilateral rTMS in late-life depression. Brain Stimulation, 2025. doi.org
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Educational information, not medical advice. Whether TMS or any treatment fits you is a decision to make with a psychiatrist who knows your history.