Advanced Depression Treatment

The targeting problem is bigger than you think

How you find the left DLPFC on someone’s skull is one of the most consequential and underappreciated variables in TMS treatment. The original method – developed by George and colleagues in 1995 – involves finding the motor cortex “hot spot” (the scalp location where TMS causes a thumb twitch) and moving the coil 5 cm forward. Simple. Also, wrong about two-thirds of the time. When Herwig and colleagues tested this with neuronavigation in 22 subjects, only 7 correctly landed on the DLPFC. The other 15 were positioned over premotor cortex. Given that standard protocol response rates hover around 50%, you have to wonder how much of the “non-response” is actually “missed the target.”

The Beam F3 method improved things considerably, using three scalp measurements to approximate a standardized electrode position. It gets within about 1.4 cm of MRI-guided targets in 95% of subjects. Structural MRI neuronavigation is more precise still. But the real frontier is functional connectivity-guided targeting – using an individual’s resting-state fMRI to find the specific DLPFC subregion maximally anticorrelated with their sgACC. Fox and colleagues demonstrated this approach identifies individualized targets that predict clinical efficacy. Weigand and colleagues prospectively validated the principle.

Drysdale and colleagues pushed even further, using fMRI in 1,188 subjects to identify four distinct depression “biotypes” defined by patterns of dysfunctional connectivity. These biotypes predicted differential response to rTMS. A replication attempt by Dinga and colleagues was less encouraging – the biotypes weren’t statistically stable in an independent sample – but the broader principle that functional connectivity matters for targeting has held up.

How rTMS stacks up against other brain stimulation

The Mutz and colleagues network meta-analysis of 113 randomized controlled trials with 6,750 patients gives us the clearest relative efficacy rankings. Combined with absolute rates from individual modality studies, here’s what the landscape looks like:

*Open-label data – take with appropriate skepticism.

ECT remains the most potent option, but it requires general anesthesia, causes cognitive side effects – particularly short-term memory disruption – and carries significant stigma. Standard rTMS delivers lower response rates but with no anesthesia, no cognitive effects, and substantially lower cost. That cognitive safety profile is rTMS’s single biggest advantage over ECT.

tDCS – transcranial direct current stimulation – is the gentlest option, using 1–2 milliamps of direct current to shift neuronal excitability at a subthreshold level. It cannot fire neurons. It’s the only modality heading toward home use, with the Flow FL-100 receiving FDA approval in December 2025 for moderate-to-severe depression. More on this later.

What a session actually feels like

You sit in a reclining chair, fully awake, no sedation. The technician positions a magnetic coil against the left side of your head and secures it. Earplugs go in – the coil is loud.

Then it starts: a rapid-fire clicking, accompanied by a sensation patients variously describe as “a woodpecker tapping on your skull,” “someone flicking your scalp really fast,” or “a little metal bird.” During the 4-second bursts, you feel a rhythmic tapping at the stimulation site, sometimes with mild involuntary facial twitching. During the 26-second rest periods, nothing. This repeats for 37 minutes with the standard protocol, or about 3 minutes with theta burst stimulation.

The first session is the worst. Scalp discomfort hits 20–40% of patients, headache 5–23%. Most people say both diminish substantially by session 3–5 as scalp nerves accommodate. By the second week, many patients describe sessions as boring rather than uncomfortable. People watch TV, listen to podcasts, chat with the technician, or zone out. You walk out and drive yourself home.

Improvement typically follows this pattern: weeks 1–2 show minimal subjective change, maybe slightly better sleep or energy. Weeks 3–4 are when most patients notice meaningful shifts – improved social engagement, reduced emotional reactivity, renewed interest in things. Some patients experience a “TMS dip” – a temporary worsening in the first week – that doesn’t predict poor outcome. Weeks 5–6 consolidate the full effect. Some patients are late responders who don’t meaningfully improve until after session 30. A Massachusetts General Hospital study showed extending treatment beyond 36 sessions in non-responders still yielded 53.6% response and 32.1% remission.

The important caveats

Let’s be real about the limitations. All pivotal SAINT data comes from a single site (Stanford). The RCT was stopped at interim analysis – 29 treated of the 60 planned. The RCT excluded patients who had previously failed TMS. Remission rates attenuate over time: the open-label 90% dropped to ~60–70% at one month; the RCT’s 79% fell to ~46% at four weeks. Average remission duration was 11 weeks, response duration 15 weeks. Senior authors hold equity in Magnus Medical and are named inventors on Stanford IP. The ongoing Open Label Optimization trial – up to 1,000 patients across multiple US sites – will provide the first multi-center data. That trial will be decisive.

Availability, cost, and insurance reality

Magnus Medical, founded in 2020 by former Stanford Brain Stimulation Lab members, holds the exclusive commercialization license. The FDA cleared their system in September 2022 with Breakthrough Device designation. Commercial launch began April 2024.

The price: $30,000–$36,000 out of pocket. Medicare will reimburse hospitals $19,703 for the full protocol (effective July 2025), with an additional New Technology Add-on Payment of up to $12,675 for inpatient treatment. Independence Blue Cross has added SAINT as “medically necessary.” But for most patients at most clinics, this is still self-pay.

Here’s the thing though – numerous clinics now offer “SAINT-like” accelerated iTBS protocols without the proprietary Magnus system or fMRI targeting, at substantially lower cost ($9,000–$12,000). The Clinical TMS Society has explicitly cautioned that “the efficacy of off-label SAINT-like protocols without neuronavigation or targeting methodology consistent with the FDA-cleared Magnus Medical SAINT Neuromodulation System is unknown.” Translation? They might work just as well, they might not, and nobody’s done the study to find out.

Why the drugs matter

ONE-D’s pharmacological enhancement isn’t window dressing – it’s the mechanistic core of how 12,000 pulses in one day can achieve what SAINT needs 90,000 pulses over five days to accomplish.

D-cycloserine (DCS) is a partial agonist at the glycine modulatory site on the NMDA receptor. NMDA receptor activation is the upstream gate for long-term potentiation – the synaptic strengthening that TMS is trying to induce. Brown and colleagues showed DCS significantly enhanced the brain’s response to rTMS in a crossover study of healthy adults. The landmark clinical translation came from a double-blind RCT in 50 depression patients: DCS 100 mg combined with iTBS produced 73.9% response versus 29.3% for iTBS plus placebo and 39.1% vs. 4.2% remission. DCS more than doubled the response rate to standard iTBS.

DCS has a longer history augmenting learning-based therapies. Ressler and colleagues first showed it enhanced exposure therapy for phobias in 2004, and a large meta-analysis of over 1,000 patients confirmed a small but significant augmentation effect across anxiety disorders.

Lisdexamfetamine (Vyvanse, 20 mg) is a prodrug of dextroamphetamine that increases prefrontal dopamine and norepinephrine release. Dopamine is critical for synaptic potentiation – you need D1 receptor coactivation for robust cortical long-term potentiation. A retrospective study found that psychostimulant use was associated with enhanced rTMS outcomes. In the ONE-D context, the low-dose lisdexamfetamine increases prefrontal catecholamine tone, potentially amplifying the plasticity window during a 9.5-hour stimulation marathon. Downar’s team is investigating whether lisdexamfetamine is strictly necessary – early reports suggest DCS alone may be sufficient.

How ONE-D compares to SAINT

The comparison is striking:

This suggests that pharmacological enhancement of neuroplasticity may compensate for less precise targeting and fewer total pulses – a trade-off with enormous implications for access and cost.

A propensity-matched follow-up study compared 106 single-day TMS patients to 191 matched standard 36-day TMS patients. Results strongly favored single-day: remission 49.1% vs. 25.1%, response 71.7% vs. 56.0%. Critically, effects were robust across four protocol variants – with different targets, different intersession intervals, and even different NMDA agonists – suggesting the core principle is robust.

The necessary skepticism

Let’s keep it real about ONE-D’s limitations. This is a retrospective, open-label case series with no control group and n=32. Thirteen of those 32 were prior TMS responders. Multiple authors hold equity in the companies commercializing the protocol. The delayed response – peaking at 6 weeks rather than immediately – is scientifically interesting but means placebo and expectancy effects can’t be excluded without a sham-controlled trial. The expectancy effects for a novel, intensive, single-day treatment that involves taking stimulants and sitting in a brain stimulation chair for 9.5 hours are going to be massive.

A properly powered RCT would need double-blind sham control, factorial design to isolate contributions of DCS, lisdexamfetamine, and acceleration, multi-site enrollment, and at least 50–100 patients per arm. Until that happens, the evidence is promising but not definitive.

ONE-D is currently available primarily through NeuroStim TMS Centers (nationwide, headquartered in Seattle) and Cognitive FX (Provo, Utah, which adds fMRI guidance at $9,000–$12,000). Washington Interventional Psychiatry in D.C. also offers it. Insurance does not cover it.

OCD

BrainsWay’s deep TMS system was cleared for OCD in August 2018 – the first non-invasive device cleared for this indication. The protocol differs from depression TMS in almost every way: it targets the medial prefrontal cortex and anterior cingulate (not the left DLPFC), uses a different coil, and – most distinctively – precedes each session with individualized symptom provocation. The clinician deliberately triggers your OCD anxiety to activate the relevant circuits before stimulating them. This isn’t just passive stimulation; it’s priming the OCD circuit before attempting to modulate it.

The pivotal trial by Carmi and colleagues randomized 99 OCD patients across 11 centers. Response rate: 38.1% active versus 11.1% sham at 6 weeks, rising to 45.2% versus 17.8% at one-month follow-up. Real-world post-marketing data from 219 patients across 22 sites showed 52.4% sustained response. Not a cure, but a meaningful difference for people who’ve exhausted other options.

PTSD

TMS is not FDA-cleared for PTSD. BrainsWay holds European certification and is conducting pivotal trials, but no large sham-controlled US trial has been completed. International guidelines assign Level B evidence (probable efficacy) for high-frequency rTMS of the right DLPFC. Studies are predominantly small and open-label. About 8.7% of US TMS clinics offer off-label TMS for PTSD. The evidence trajectory looks like depression TMS circa 2005 – heading somewhere, but not there yet.

Chronic pain

High-frequency rTMS of the primary motor cortex contralateral to the painful side has Level A evidence (definite efficacy) per international guidelines for neuropathic pain. Conditions that respond best include post-stroke central pain, spinal cord injury pain, and trigeminal neuropathic pain. Fibromyalgia gets Level B. However, the underlying studies are small and heterogeneous, and no pivotal trial sufficient for FDA clearance has been completed.

Cognitive enhancement in healthy people

Let’s be real: mostly hype. Some single-session studies report small improvements in specific tasks like working memory and reaction time, but effects are typically tiny, short-lived, and unreplicated. Silicon Valley biohacking culture has embraced brain stimulation enthusiastically, but the evidence hasn’t kept pace with the marketing.

Psychotherapy during or right after sessions

The most compelling data comes from Donse and colleagues: 196 depression patients received simultaneous rTMS plus CBT-based psychotherapy – therapist present in the chair, session lasting 45 minutes total with 20 minutes of TMS. Results: 66% response, 56% remission, with 60% sustained remission at 6 months. These numbers substantially exceed typical rTMS-alone outcomes (~30% remission).

The logic is compelling: if rTMS enhances prefrontal function and top-down regulation through DLPFC stimulation, and CBT teaches cognitive reappraisal skills that depend on these same prefrontal circuits, delivering both simultaneously could be synergistic. No large-scale RCT has directly compared TMS+CBT versus TMS alone, but the signal is strong enough that many clinics now integrate psychotherapy into TMS treatment.

Medication timing

A 2024 systematic review found a “large significant decline in formal depression scores when rTMS is combined with SSRIs compared to SSRI monotherapy,” with SSRIs outperforming SNRIs as combination partners. Here’s the thing though – benzodiazepines may actually interfere. GABAergic activity dampens the synaptic potentiation mechanisms that TMS relies on. Clinical consensus recommends medications be stable for 2–4 weeks before starting TMS to differentiate effects, but the treatment period may be an excellent time to optimize an SSRI.

Exercise

Both exercise and rTMS increase BDNF through convergent pathways. No published RCTs specifically test exercise plus TMS synergy, but the biological rationale is among the strongest untested hypotheses in the field. Pro tip: maintain or start a regular aerobic exercise program during your TMS course. The cost is zero and the potential upside is real.

The bigger picture

The ONE-D protocol’s d-cycloserine plus lisdexamfetamine combination is the most explicit attempt to pharmacologically widen the neuroplasticity window during TMS. But it fits within a larger pattern: DCS has been used to augment exposure therapy since 2004, ketamine plus TMS combinations are being explored (a 2023 review of 11 studies showed “superior efficacy of combined TMS + ketamine over monotherapy”), and SSRIs themselves may enhance TMS-induced plasticity. The principle is the same: if TMS induces a state of enhanced plasticity, anything that amplifies or extends that state should improve outcomes. The field is converging on pharmacologically enhanced brain stimulation as the next major paradigm.

Finding a provider and avoiding red flags

Treatment must be prescribed and supervised by a board-certified psychiatrist. The initial motor threshold determination must be performed by a physician or qualified healthcare professional. Subsequent sessions can be administered by a trained TMS technician under physician supervision.

Red flags:

• Clinics claiming 90%+ success rates without specifying whether they mean response or remission (real-world monotherapy data: ~50–60% response, ~30% remission)
• No psychiatrist involvement in treatment planning
• No standardized symptom tracking (PHQ-9, HAMD, or MADRS at regular intervals)
• High-pressure self-pay sales when insurance may cover treatment

What the money actually looks like

US out-of-pocket cost for a standard 30–36 session course: $6,000–$15,000, with per-session costs of $200–$500. With insurance, typical copays run $10–$70 per session, putting total out-of-pocket at $360–$2,500 depending on deductible status.

Major insurers now cover rTMS for treatment-resistant depression, but requirements vary:

• Aetna: 2 failed antidepressant trials plus 1 augmentation
• Cigna: 2 antidepressants from 2 different classes
• Optum: 4 failed medications
• HealthNet: 4 antidepressants from 2+ classes (most stringent)
• Medicare: Covered under Part B
• California Medicaid (Medi-Cal): Added routine coverage in August 2024 for patients 15+

Prior authorization is almost always required.

In the UK, despite NICE guidance finding “no major safety concerns” and recommending rTMS as a treatment option, NHS availability is extremely limited. Only a handful of NHS Trusts offer it – Northamptonshire, Camden and Islington, Cumbria/Northumberland/Tyne and Wear, and Somerset. Some regions explicitly deem TMS “low priority for funding.” Most UK patients access rTMS privately.

Side effects: what’s real and what’s rare

The most common side effect is headache (5–23% of patients), followed by scalp discomfort at the stimulation site (20–40%). Both typically diminish by session 3–5. The most serious risk is seizure, occurring at a rate of roughly 1 in 10,000 sessions (slightly higher for deep TMS H-coils). The pivotal O’Reardon trial reported zero seizures.

Absolute contraindications: ferromagnetic implants near the head (aneurysm clips, cochlear implants, metal plates) and implanted electrical devices (pacemakers, vagus nerve stimulators, deep brain stimulators). No cognitive side effects – multiple studies confirm this, and it’s the single biggest advantage over ECT.

Harm reduction for DIY users

The Bikson and colleagues safety consensus paper reviewed over 33,200 sessions across more than 1,000 subjects using conventional parameters (up to 40 min, up to 4 mA, up to 7.2 Coulombs) and found zero serious adverse events or irreversible injuries. That’s genuinely reassuring. But “conventional parameters” is doing a lot of work in that sentence.

The biggest real-world risk is skin burns from poor electrode contact – when sponge electrodes dry out or make uneven contact, current concentrates at edges. DIY users who reuse disposable pads or improvise conductive solutions face elevated risk. Electrode placement matters enormously – moving electrodes even 1–2 cm changes which neural networks receive stimulation. More is not better: research has shown partially non-linear effects – doubling current does not double the benefit and may actually reverse the effect. Stick to 2 mA for 20–30 minutes if you’re going to do this at all.

DIY rTMS, by contrast, is genuinely dangerous. rTMS devices require high-voltage capacitor banks, precisely engineered coils, and strict safety parameters specifically designed to prevent seizures. You cannot determine your own motor threshold. YouTube “brain ray” tutorials are promoting devices that pose real risks of seizure, electrical shock, and unpredictable neuropsychiatric effects. The safety margin for rTMS is narrow in a way that tDCS’s is not.

Theta burst stimulation already changed the math

The Blumberger THREE-D trial – 414 patients across 3 Canadian university hospitals – showed that iTBS was non-inferior to standard 10 Hz rTMS for treatment-resistant depression. The clinical significance: equivalent outcomes in ~3 minutes versus ~37.5 minutes per session. iTBS mimics endogenous theta-gamma phase-amplitude coupling – the same neural patterns critical for synaptic plasticity and memory consolidation. This biomimetic patterning may explain why 600 pulses of iTBS achieves what 3,000 pulses of 10 Hz requires. iTBS was FDA-cleared in 2018 and is now the backbone of every accelerated protocol.

Personalized targeting

The theoretical case is settled: generic scalp-landmark targeting misses the optimal DLPFC subregion in most patients, and individuals whose stimulation site happens to be maximally anticorrelated with the sgACC respond best. The practical case is messier. A 2023 RCT tested connectivity-guided iTBS versus standard targeting – both reduced symptoms, but connectivity guidance didn’t clearly outperform standard targeting. A large 2025 preprint found accelerated TMS worked “with or without fMRI guidance” but that fMRI guidance “significantly improved outcomes.” The SAINT and ONE-D results point in the same direction: targeting precision matters, but pharmacological augmentation may compensate for imprecise targeting. fMRI-guided personalization is likely 3–5 years from becoming standard of care, limited by cost, specialized software, and the need for more definitive data.

Closed-loop stimulation

Current TMS is “open-loop” – it fires pulses on a fixed schedule regardless of what the brain is doing at that instant. Closed-loop stimulation uses real-time EEG to detect the brain’s oscillatory state and triggers pulses at moments of optimal neural receptivity. Motor cortex studies show TMS delivered at the trough of certain brain rhythms produces larger effects than stimulation at the peak. This is firmly in the proof-of-concept stage – clinical applications are likely 5–10 years from routine use, with major technical challenges remaining.

The compression trajectory

The arc is clear: 6 weeks (2008 standard) to 5 days (SAINT, 2020) to 1 day (ONE-D, 2025). Each compression required an innovation: iTBS enabled shorter sessions, spaced-repetition scheduling enabled multiple daily sessions, pharmacological enhancement compensated for fewer total pulses. ONE-D’s achievement of comparable results with only 12,000 pulses versus SAINT’s 90,000 – by adding two cheap generic drugs – suggests we may be approaching a pharmacologically-augmented minimum effective dose.

But here’s what matters most: depression treatment is moving from chronic pharmacotherapy (daily pills for months or years) toward acute intervention (hours to days of intensive neuromodulation). If closed-loop targeting arrives and neuroplastogen cocktails continue to improve, the possibility of a single-session, few-hour treatment for an acute depressive episode stops being science fiction. It’s an engineering problem.