For patients living with Depression — especially those who have not responded to medications — transcranial magnetic stimulation (TMS) has become one of the most important noninvasive treatment options available. A landmark randomized clinical trial published in JAMA Psychiatry, known as the FOUR-D trial, provides strong evidence that a newer, significantly faster form of TMS delivers the same antidepressant effects as traditional treatment. For older adults with treatment-resistant Depression in particular, the findings carry meaningful implications for how care can be delivered more efficiently without sacrificing outcomes.
Why This Matters for Older Adults
Major depressive disorder remains one of the leading causes of disability worldwide, and the challenge is especially pronounced in older adults. In this population, response rates to antidepressants are lower, side effects are more common, and medical and cognitive complications make treatment more complex. Nonresponse to first-line antidepressants in older adults ranges from 55% to 81% — a striking figure that underscores how urgently better options are needed.
The FOUR-D trial was designed specifically with this population in mind, enrolling adults aged 60 and older with treatment-resistant Depression. Its findings are directly applicable to real-world clinical practice.
Understanding the Two Treatments
Standard repetitive TMS (rTMS) works by delivering magnetic pulses to the left dorsolateral prefrontal cortex (DLPFC) — the brain region most closely associated with mood regulation — with additional stimulation to the right DLPFC in bilateral protocols. A standard bilateral rTMS session takes approximately 47.5 minutes.
Theta burst stimulation (TBS) is a newer form of TMS that mimics natural brain rhythms associated with learning and memory, delivering stimulation in rapid, patterned bursts. Intermittent TBS (iTBS) is applied to the left DLPFC, and continuous TBS (cTBS) to the right. The key difference is efficiency: a full bilateral TBS session takes approximately 4 minutes.
The FOUR-D trial set out to determine whether this dramatically shorter protocol was noninferior — meaning not meaningfully worse — than standard rTMS.
What the Study Found In Theta Burst TMS for Older Adults
The trial enrolled 172 adults aged 60 and older, all with a confirmed diagnosis of major depressive disorder and inadequate response to at least one antidepressant trial. Participants were randomized to receive four to six weeks of either standard bilateral rTMS or bilateral TBS, five days per week. The primary outcome was change in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS).
Theta burst TMS for older adults was robustly noninferior to standard rTMS on the primary outcome, with an adjusted difference of 1.55 points favoring TBS — well within the predefined noninferiority margin. MADRS scores improved from a mean of 25.7 to 15.8 in the TBS group, compared to 25.6 to 17.3 in the rTMS group.
The secondary outcomes reinforced this finding. Response rates — defined as at least 50% improvement in symptoms — were 44.3% for TBS compared to 32.9% for standard rTMS. Remission rates were comparable between groups at 35.4% and 32.9% respectively. Noninferiority was demonstrated across all clinician-rated and self-reported measures at every assessment point, including 12 weeks after treatment ended.
A remission rate of 35.4% in a population of older adults with treatment-resistant Depression — many of whom had failed two or more antidepressant trials — is a clinically meaningful outcome worth emphasizing.
Safety and Tolerability
Both treatments were well tolerated, with high retention rates during active treatment. Headache, dizziness, and nausea were reported at similar rates across both groups, and there were no serious adverse events related to either treatment.
This study did find, however, that theta burst TMS for older adults was associated with slightly higher pain ratings than standard rTMS, particularly with right-sided cTBS where stimulation is delivered in a continuous 40-second train. This is worth knowing going in. Importantly, however, the higher pain ratings did not translate into higher dropout rates — retention remained strong in both groups — and many patients find that discomfort decreases as they acclimate to treatment in the first few sessions.
On cognitive safety, which is a particularly important consideration in older adults, the study found no evidence of cognitive worsening in either group, and no differences between TBS and rTMS on any cognitive measure. This is a meaningful distinction from electroconvulsive therapy (ECT), where cognitive side effects can occur.
What a 4-Minute Session Actually Means
The practical significance of the session length difference is easy to underestimate. Reducing a treatment session from 47.5 minutes to 4 minutes represents more than a 90% reduction in chair time. For older adults managing other medical appointments, transportation challenges, fatigue, or caregiver responsibilities, that difference can determine whether completing a full course of treatment is realistic at all.
Shorter sessions also increase clinic capacity, meaning more patients can be seen — an important consideration as demand for TMS continues to grow. And for patients who have previously found standard TMS sessions physically or logistically difficult, theta burst TMS for older adults offers a genuinely more accessible path to the same outcomes.
Personalized Treatment at Mid City TMS
The FOUR-D trial adds to a growing body of evidence supporting theta burst TMS for older adults as a clinically equivalent alternative to standard rTMS — not a compromise, but a legitimate option with its own practical advantages. At Mid City TMS, Dr. Bruno offers both traditional rTMS and theta burst stimulation protocols, allowing treatment to be tailored to each patient’s clinical needs, schedule, and response.
Not every patient is the same, and not every protocol is the right fit for every person. If you are an older adult living with Depression that has not responded to medication, or if you have questions about which TMS approach may be appropriate for you, we are happy to consult with you.
Contact us today to learn more.
Sources
- Blumberger DM, Mulsant BH, Thorpe KE, et al. Effectiveness of Standard Sequential Bilateral Repetitive Transcranial Magnetic Stimulation vs Bilateral Theta Burst Stimulation in Older Adults With Depression: The FOUR-D Randomized Noninferiority Clinical Trial. JAMA Psychiatry. 2022;79(11):1065–1073. doi:10.1001/jamapsychiatry.2022.2862
- Quilty, Lena C et al. “The structure of the Montgomery-Åsberg depression rating scale over the course of treatment for depression.” International journal of methods in psychiatric research vol. 22,3 (2013): 175-84. doi:10.1002/mpr.1388