TMS Outperforms Medication in Study of Treatment-Resistant Depression

NeuroStar TMS Therapy

Source: Grant H Brenner

Transcranial magnetic stimulation (TMS, or "rTMS" for "repetitive TMS") received an indication for treating major depressive disorder in 2008. Since then, research and clinical experience with TMS has been growing, and recent applications include rapid "accelerated" TMS for depression¹ and indications for obsessive-compulsive disorder, depression in teens 15 years of age and older (approved currently with NeuroStar TMS), and for smoking cessation.

Briefly (see reference 1 below for more detail), TMS applies a fluctuating magnetic field, generated by an electromagnetic coil, to stimulate key brain regions associated with various clinical conditions.

During TMS, a magnetic coil is placed against the scalp, and treatment is administered over a period of time for multiple sessions, requiring no sedation or anesthesia, no need for recovery following the procedure, and an excellent safety profile. For depression, the area treated is typically the left dorsolateral prefrontal cortex (LDLPFC). TMS increases activity in this key "executive function" area, leading to beneficial changes throughout brain networks related to emotion regulation, decision-making, cognition, and other key functional areas.

Prior Data on TMS

TMS has been found to be safe and effective, with complete resolution in more than 70 percent of people with depression for some protocols, and correspondingly high response rates, defined as at least a 50 percent reduction in symptoms. TMS tends to be durable, though some patients become depressed again, often with partial symptoms, and benefit from re-treatment or maintenance.

By contrast, data on medications shows that up to 36 percent of patients have a full resolution of depression overall—given multiple medication trials—with less than 30 percent responding well with the first medication. About one-third don't see benefit with the first medication, requiring multiple time-consuming medication trials, during which depression tends to become entrenched. With each additional medication trial, the remission rate gets lower and side effects ("adverse events") rise, according to the STAR-D trial.² So if we look at the results for TMS and the results for clinical depression, TMS response rates are very good. However, there has been limited direct head-to-head research comparing the two in the same clinical trial.

TMS and Medication Head-to-Head

Researchers in the Netherlands, as reported in their study³ in the American Journal of Psychiatry (Dalhuisen et al., 2024), conducted a multi-center study to directly compare TMS with medications for patients with treatment-resistant depression. Eighty-nine patients were randomized to receive either TMS or a medication switch after having failed at least two prior medication trials. All patients were in psychotherapy. The TMS protocol used was similar to standard protocols: eight weeks of treatment with high-frequency stimulation of the LDLPFC.

Patients assigned to the TMS group showed significantly better responses to treatment compared with the medication group. Response rates were 37.5 percent versus 14.6 percent, and remission rates were 27.1 percent versus 4.9 percent. Qualitatively, TMS responders showed greater improvement in anxiety and loss of ability to enjoy things ("anhedonia") versus those receiving medications, with similar improvement in rumination, cognitive reactivity, and sleep problems.

Implications

This work supports clinical experience and prior indirect data that TMS outperforms medications for treatment-resistant depression, looking specifically at patients who had received psychotherapy and failed at least two prior medication trials. Notably, remission rates for TMS even after failed medications were comparable to remission rates for patients in the STAR-D study receiving a first medication. Furthermore, patients in the medication arm of the current study did very well less than 5 percent of the time with full symptom resolution, and less than 15 percent had a partial response.

A more pressing question is whether TMS should be offered much earlier for people suffering with clinical depression. Current accelerated TMS protocols, even with treatment-resistant depression, achieve remission in more than 70 percent of patients in one-week treatment protocols. Standard TMS is typically 36 sessions, lasting four to six weeks.

By contrast, the 30 percent response to a first medication often takes two to three months, with initial doses acting within three to eight weeks, and then increasing doses to see what the full clinical effect will be. If a medication switch is required, this entails additional weeks and sometimes months of time and worsening side effect risk.

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A strong case can be made to treat with TMS early in the clinical depression treatment algorithm, alongside therapy and perhaps as a first or second choice. The reasoning is straightforward: TMS will either work or not work in a short span of time. If it works, medication may be minimized, as maintenance medication may still be of benefit. If it does not work, additional, more time-consuming medication treatment can be instituted. This would save time to resolution or reduction of symptoms, enable faster recovery and return to well-being and function, and also prevent depression from becoming entrenched. As depression goes untreated, suffering increases and the chances of recovery go down.

Future research will be required to test whether TMS compares favorably with medications, either as a first-line alternative or as a choice instead of ongoing medication trials. As it stands, TMS is recommended by the American Psychiatric Association⁴ (Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 2010) as a reasonable alternative to a second medication, and is indicated in adolescent depression as a first-line option. TMS stands alongside conventional treatments and emerging treatments such as ketamine as an important approach given its safety and efficacy.

Disclaimer: Dr. Brenner provides TMS therapy using the NeuroStar system and also treats patients with psychotherapy and medication.