If your depression hasn't responded to multiple antidepressants, you're not alone—and you're not out of options. About 30% of people with depression don't achieve adequate relief from their first medication, and for those who've tried multiple treatments without success, finding the right path forward can feel overwhelming.
This comprehensive guide examines all evidence-based treatments for treatment-resistant depression (TRD) with the latest 2025 research, including Stanford's groundbreaking SAINT TMS durability study. You'll discover actual remission rates, how long benefits last, what maintenance each treatment requires, and realistic cost comparisons—everything you need to make an informed decision about your next steps.
Whether you're considering brain stimulation therapies like SAINT TMS or ECT, evaluating rapid-relief options like ketamine, exploring specialized psychotherapy approaches, or trying to understand why your antidepressants stopped working, this guide provides the comprehensive comparison you've been searching for.
Reading time: 15 minutes | Last updated: November 2025
Treatment-resistant depression isn't a different type of depression—it's what we call depression that hasn't responded adequately to standard treatments. Understanding whether you meet the criteria for TRD is the first step toward finding more effective options.
You're generally considered to have treatment-resistant depression if you've tried two or more antidepressant medications at adequate doses for sufficient duration (typically 6-8 weeks each) without achieving satisfactory improvement. The medications need to be from different classes, and you need to have taken them correctly as prescribed.
This definition matters because it determines which advanced treatment options you may qualify for, including specialized brain stimulation therapies and intensive psychotherapy programs.
If you're struggling with TRD, you're far from alone. The statistics reveal just how common this challenge is:
30% of people with depression don't respond adequately to their first antidepressant
50-60% don't achieve full remission even after multiple medication trials
The landmark STAR*D study found that with each successive medication trial, your chances of response decrease significantly
After four different medication approaches, only 2.7% maintained stable remission through 12 months
These numbers explain why finding alternatives to continued medication trials becomes so important for many patients.
Depression that doesn't respond to multiple medications often reflects deeper issues than simple neurotransmitter imbalances. Research points to several factors:
Neural circuit dysfunction: Disrupted connections between brain regions involved in mood regulation, particularly between the prefrontal cortex and deeper emotional centers
Genetic factors: Variations in how your body metabolizes medications or in receptor sensitivity
Chronic stress effects: Long-term depression can actually change brain structure and function, making it harder for medications alone to restore normal activity
Inflammation: Emerging research shows that some treatment-resistant depression involves immune system activation that standard antidepressants don't address
This understanding is what makes treatments like SAINT TMS—which directly target and strengthen weakened neural circuits—potentially more effective than trying yet another medication. Learn more about why antidepressants stop working and what happens in your brain when standard treatments fail.
Before diving into each treatment, let's look at how all your options compare across the factors that matter most: how well they work, how quickly you'll feel relief, how long benefits last, and what ongoing commitment each requires.
This comparison table gives you the big picture. Understanding these differences helps you evaluate which treatments align with your specific needs, timeline, and life circumstances.
Not sure which treatment path is right for you?
Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) represents the most significant advance in depression treatment in over a decade. If you're wondering whether the remarkable success rates you've heard about are real—and more importantly, whether they last—here's what the latest research reveals.
SAINT isn't just "faster TMS." It's a fundamentally different approach built on three key innovations:
1. Personalized Brain Mapping: Instead of using scalp landmarks that achieve less than 50% accuracy, SAINT uses functional connectivity MRI (fcMRI) to map YOUR unique brain networks. The imaging identifies the exact spot in your left dorsolateral prefrontal cortex that's most disconnected from your subgenual anterior cingulate cortex—the specific circuit disruption that drives depression. Neuronavigation software then guides magnet placement with near-100% accuracy.
2. Accelerated, High-Dose Protocol: You receive 1,800 pulses per session, 10 sessions per day (with 50-60 minute breaks between sessions), for 5 consecutive days. That's 90,000 total pulses compared to the 18,000-20,000 delivered over 6-9 weeks with standard TMS. This concentrated dosing creates more powerful neural circuit changes.
3. Optimized Stimulation Parameters: SAINT uses intermittent theta burst stimulation (iTBS), a more efficient pattern that delivers the same therapeutic effect in a fraction of the time—each session takes just 10 minutes rather than 30-40 minutes.
This combination of precision targeting, accelerated delivery, and optimized parameters explains both the dramatic response rates and the speed of relief.
The numbers from the latest Stanford studies are remarkable:
70-90% of patients achieve full remission within one week of completing the 5-day protocol
Average time to feeling relief: just 3 days
These remission rates are 2-3 times higher than standard TMS (30-36%)
SAINTS even outperforms ECT (48% remission), previously considered the most powerful treatment for severe depression
For patients experiencing suicidal thoughts, the results are particularly striking: all 21 participants in the open-label study reported suicidal ideation before treatment, and none reported suicidal thoughts after completion
When you've been suffering for months or years, achieving even partial remission and getting your life back in less than a week can be transformative.
This is the critical question, and a 2025 durability study published in Brain Stimulation provides the most comprehensive answer yet.
Without any maintenance treatment: Of the 32 patients who achieved remission, 47% maintained their remission at the 12-week (3-month) mark. The median time patients stayed well was 105 days (about 3.5 months). This natural durability is comparable to ECT and standard TMS when no follow-up care is provided.
With personalized maintenance treatment: Here's where SAINT becomes game-changing. A separate 2024 continuation therapy study showed that when patients received algorithm-guided maintenance SAINT sessions triggered by early warning signs of relapse, 86% of participants maintained remission over 12 months.
The maintenance burden was remarkably light:
68.9% of the patients required retreatment courses only for 1-2 days of of iTBS sessions
Your initial brain scan remains effective for at least 12 months, eliminating the need for repeated fMRI imaging
Retreatment can begin within days when early warning signs appear, preventing full relapse
This means you're potentially looking at staying well with just a couple days of treatment every few months when needed—rather than daily medications, weekly ketamine infusions, or monthly ECT sessions.
Have failed two or more antidepressant trials (meeting TRD criteria)
Experience moderate to severe depression significantly impacting your daily functioning
Need rapid relief due to symptom severity or life circumstances
Can commit to the intensive 5-day protocol (10 daily sessions with breaks)
Are willing to monitor symptoms and return for brief maintenance when early warning signs appear
Have access to a SAINT-capable center (currently limited)
Can manage the upfront cost or qualify for Medicare coverage
Contraindications and considerations: iTBS cannot be performed if you have certain types of metal implants near your head, a history of seizures, or are pregnant. Your psychiatrist will conduct a thorough screening to ensure safety.
The primary barriers to SAINT remain cost and availability:
Current cost: $28,000-36,000 for the initial 5-day treatment course, which includes the fMRI brain mapping, all 50 treatment sessions, and neuronavigation setup.
Medicare coverage: Beginning July 2025, Medicare will cover SAINT at $19,703—a significant step toward broader access. This coverage could influence private insurance companies to follow suit.
Limited availability: Currently, fewer than 20 clinics in the United States offer the complete SAINT protocol with fMRI mapping and neuronavigation. This number is growing as more centers invest in the required technology and training.
When evaluating cost, consider that retreatment courses are significantly less expensive than the initial treatment since you don't need new brain imaging, and most retreatments require only 1-2 days rather than the full 5-day protocol.
Before accelerated fMRI Guided TMS came along, standard TMS represented a major breakthrough for treatment-resistant depression. While it doesn't achieve the same remission rates as the accelerated approach, it remains an important option—particularly if you prefer a gradual approach, want insurance coverage, or can't access a personalized TMS treatment in your area.
FDA-approved since 2008, standard repetitive transcranial magnetic stimulation (rTMS) uses magnetic pulses to stimulate nerve cells in the brain region involved in mood regulation. The treatment is non-invasive—the magnetic coil is placed against your scalp, requiring no surgery, anesthesia, or sedation.
Typical protocol:
Daily weekday sessions for 6-9 weeks (36-40 total sessions)
About 3,000 pulses per session, taking 30-40 minutes
Target location determined by the "F3 position"—a scalp measurement system
Total of approximately 18,000-20,000 pulses over the full treatment course
The gradual, extended protocol allows your brain to adapt slowly to the changes, which may explain both the longer timeline to feeling results and the different maintenance needs compared to SAINT.
The evidence base for standard TMS is extensive, with outcomes from thousands of patients:
30-36% remission rate in treatment-resistant depression populations
Response rates (significant improvement without full remission): 40-58%
Time to response: typically 4-6 weeks, though some patients notice changes earlier
Results are better than continued medication trials for those who've already failed multiple antidepressants
Lower remission rates than guided TMS (30-36% vs 70-90%), but significantly more accessible and affordable
While one-third achieving full remission may seem modest compared to guided fMRI TMS, remember that for medication-resistant depression, this represents meaningful improvement over trying yet another antidepressant with diminishing odds of success.
The durability picture for standard TMS reveals the critical importance of continuation care:
With continuation medications and monitoring:
50% sustained response rate at 1 year
20% relapse rate at 6 months
Staying on antidepressants after successful TMS significantly improves durability
Without any continuation treatment:
80% of patients relapsed when no follow-up protocol was implemented
This finding highlights that TMS—like SAINT and ECT—creates changes that may need reinforcement
Typical maintenance protocols:
Gradual tapering from 3 times weekly to once monthly over several months
Continued monthly or biweekly sessions for extended periods
When symptoms worsen, reintroducing TMS shows an 84.2% success rate in re-achieving benefit
Total maintenance commitment: ongoing monthly appointments, potentially for years
The maintenance burden is heavier than guided TMS (monthly vs quarterly), but lighter than weekly ketamine infusions or daily medication management with regular psychiatrist visits.
Source: https://pmc.ncbi.nlm.nih.gov/articles/PMC7675193/
Standard TMS makes sense if you:
Cannot access or afford fMRI Guided TMS
Have failed 1-2 medications but don't have severe, highly resistant depression
Prefer gradual improvement over the intensive 5-day SAINT protocol
Want an FDA-approved, insurance-covered option (most insurers cover standard TMS after documented medication failures)
Can commit to 6-9 weeks of daily weekday appointments
Are comfortable with lower remission odds (30-36%) in exchange for broader availability
Many patients who don't achieve full remission with standard TMS still experience meaningful improvement in functioning and quality of life.
Source: https://pubmed.ncbi.nlm.nih.gov/30344109/
Full treatment course: $6,000-12,000 for 36-40 sessions
Insurance coverage: Most insurance companies, including Medicare, cover standard TMS for treatment-resistant depression after you've tried and failed a minimum number of antidepressants (typically 4 different medications). Prior authorization is required, and your psychiatrist will need to document your treatment history.
Out-of-pocket costs: If you have insurance coverage, your costs depend on your deductible and coinsurance. Many patients pay $1,000-3,000 out of pocket after insurance. Without insurance, payment plans are typically available.
Despite decades of newer treatments, electroconvulsive therapy remains the most powerful option for certain types of severe depression. If you're considering ECT or it's been recommended to you, understanding when it's truly the best choice—and when alternatives might work as well—is essential.
Psychotic depression: When depression includes delusions or hallucinations, ECT achieves better outcomes than any other treatment
Catatonic depression: Severe psychomotor disturbance where you may be immobile or show unusual behaviors
Immediate life-threatening situation: Active plans or intent to die requiring the fastest possible response
Severe malnutrition due to inability to eat, requiring rapid intervention
Previous excellent ECT response: If ECT worked well for you in the past, it's likely to work again
Pregnancy with severe depression: ECT is considered safe during pregnancy when severe depression threatens maternal or fetal health
For these specific situations, ECT's proven track record and speed of action make it the appropriate first choice rather than experimenting with newer alternatives.
ECT's power comes from inducing a brief, controlled seizure under general anesthesia, which triggers widespread neurochemical changes in the brain:
48% remission rate in treatment-resistant depression
Response rates (significant improvement): 60-80%
Time to response: 1-2 weeks (faster than most alternatives except ketamine)
Particularly effective for older adults and those with melancholic features
Works when virtually everything else has failed
While fMRI TMS now achieves higher remission rates (70-90%), ECT has decades of evidence and remains the most powerful treatment we have for the specific situations listed above.
Source: https://pmc.ncbi.nlm.nih.gov/articles/PMC8020309/
ECT's Achilles heel is durability without follow-up care. The relapse rates without maintenance are sobering:
Without ANY follow-up treatment:
84% of ECT remitters relapse within 6 months
This is the highest relapse rate of any depression treatment
Makes continuation care absolutely essential—not optional
With continuation medications alone:
Relapse rates improve to 37.7% at 6 months and 51.1% at 12 months
The gold-standard medication combination (nortriptyline plus lithium) achieves 39% relapse at 6 months
Most relapses occur in the first 5 weeks after ECT ends
With continuation ECT (C-ECT):
37.1% relapse at 6 months in the large CORE study
Typical C-ECT schedule: weekly for 4 weeks, then biweekly for 8 weeks, then monthly maintenance
Totals about 10 sessions over 6 months initially
With BOTH continuation ECT AND medications (optimal approach):
Only 7% relapsed at 2 years (93% relapse-free survival) in landmark studies
At 5 years: 27% relapse with combination vs 82% with medications alone
This dramatic difference makes the combination approach standard of care
Who needs more aggressive follow-up: ECT durability is worse for younger patients, women, those with higher medication resistance before ECT, and those with residual symptoms after treatment. Treatment-resistant patients specifically showed 64% relapse at 12 months even with follow-up care.
The bottom line: Plan on monthly maintenance ECT for at least a year, possibly longer, along with optimized medications.
Sources: https://pubmed.ncbi.nlm.nih.gov/11255384/
https://pubmed.ncbi.nlm.nih.gov/17146008/
The memory question: This is what most patients worry about. The reality is nuanced:
Short-term memory effects are common during the treatment course—difficulty forming new memories, confusion about recent events
Most cognitive effects resolve within weeks after treatment ends
Some patients (roughly 30-50%) report persistent memory gaps for events around the treatment period
Long-term studies show no progressive cognitive decline with ongoing maintenance ECT
Bilateral electrode placement (more effective) causes more memory effects than right unilateral placement (fewer memory effects)
The anesthesia requirement: Every ECT session requires general anesthesia, which means:
Fasting before each treatment
IV placement
Brief period under anesthesia (5-10 minutes)
Recovery time afterward (30-60 minutes)
Cannot drive yourself home
Total time commitment per session: 2-3 hours
Other common side effects:
Headache (usually managed with over-the-counter pain relievers)
Muscle aches
Nausea
Confusion immediately after treatment
Safety profile: ECT is safe. The mortality rate is approximately 1 in 10,000 treatments—comparable to general anesthesia for minor procedures. But, it is probably the most risky therapy followed by ketamine discussed later in this post.
When to choose fMRI Guided TMS over ECT:
Depression is severe but not psychotic, catatonic, or immediately life-threatening
You want to avoid anesthesia and memory effects
The higher remission rate (70-90% vs 48%) outweighs ECT's longer track record for your situation
When ECT is still the better choice:
You have psychotic or catatonic features
Previous excellent response to ECT
Severity requires the most proven, powerful option
TMS or other alternatives have already failed
You're pregnant and need treatment
Per session: $300-1,000 depending on facility and geographic location
Acute course: $2,500-5,000 for initial 6-12 treatments
Continuation/maintenance: $3,600-12,000 per year if continuing monthly sessions
Insurance coverage: Medicare and most insurance companies cover ECT when medically necessary for severe, treatment-resistant depression. Prior authorization is typically required, but coverage is generally good since ECT has such a long evidence base.
Total first-year cost with maintenance: $6,000-17,000, most of which is usually covered by insurance.
If you need relief measured in hours or days rather than weeks, ketamine-based treatments offer the fastest-acting option for treatment-resistant depression. But speed comes with trade-offs in durability and ongoing commitment.
Unlike every other depression treatment that targets monoamine neurotransmitters (serotonin, norepinephrine, dopamine), ketamine works through the glutamate system and NMDA receptors. This completely different mechanism explains both why it works when other treatments have failed and why it acts so quickly.
Two forms available:
1. IV/IM Ketamine (off-label use):
Administered by infusion over 40 minutes in a clinic
Doses typically 0.5-1.0 mg/kg
Most flexible dosing and administration
Longer track record for depression treatment
Not FDA-approved for depression (off-label use)
2. Esketamine nasal spray - Spravato (FDA-approved):
The S-enantiomer of ketamine, administered as nasal spray
FDA-approved specifically for treatment-resistant depression (2019)
Self-administered at clinic under supervision
Must be combined with oral antidepressant
2-hour supervised monitoring required after each dose
Structured protocol with defined induction, optimization, and maintenance phases
Both forms show similar effectiveness:
50-70% response rate (significant improvement)
Relief within 24-72 hours—the fastest of any depression treatment
Particularly effective for treatment-resistant suicidal ideation (esketamine has FDA indication for this)
Effects peak at 24 hours post-administration
Some patients notice subtle improvements within just 2-4 hours
For someone in crisis or experiencing severe, unrelenting depression, getting meaningful relief in a day or two can be life-saving.
Source: https://pmc.ncbi.nlm.nih.gov/articles/PMC4447578/#R8
Here's the critical limitation: ketamine's effects are powerful but remarkably short-lived without ongoing treatment.
After a single infusion:
Antidepressant effect typically lasts 3-7 days
Median time to relapse: 13.2 days
Only 27% of single-infusion responders maintained response at 4 weeks
After the standard 6-infusion course (3x weekly for 2 weeks):
Median time to relapse extends to 18 days post-treatment
Some patients with repeated-dose protocols show effects lasting up to about 6 weeks
But 68-75% of patients relapsed within 6 months without ongoing treatment
For esketamine with structured maintenance:
The SUSTAIN-1 trial demonstrated 51% relapse risk reduction for stable remitters compared to stopping treatment
70% risk reduction for stable responders
Long-term safety data extends to 6.5 years of continuous treatment
Real-world 6-month outcomes from the ICEBERG study: 49.7% response rate, 27.7% remission rate
The pattern is clear: ketamine provides remarkable rapid relief, but you're essentially "renting" that relief rather than creating lasting changes. When you stop treatment, benefits disappear within weeks.
To maintain the antidepressant effects, most patients need:
For IV/IM ketamine:
Weekly infusions indefinitely (some patients can extend to every 10-14 days)
40-minute infusion plus 30-60 minutes monitoring
Regular clinic visits for the rest of your life or until you transition to another treatment
For esketamine (Spravato):
Induction phase (weeks 1-4): Twice weekly, 56mg or 84mg doses
Optimization phase (weeks 5-8): Once weekly
Maintenance phase (week 9+): Once weekly or every other week
Each visit requires 2 hours at the clinic (administration plus monitoring)
Must be combined with ongoing oral antidepressant
This maintenance burden is substantially heavier than SAINT (1-2 days every few months), standard TMS (monthly sessions), or even ECT (monthly sessions). The ongoing time and logistical commitment is significant.
When comparing the two fastest-acting treatments for TRD:
The fundamental difference: ketamine provides immediate but temporary relief requiring continuous treatment, while fMRI TMS aims to create more durable neural changes requiring only intermittent reinforcement.
IV ketamine:
Per infusion: $400-800
Initial 6-infusion course: $2,400-4,800
Ongoing weekly maintenance: $20,800-41,600 per year
Total first year: $23,000-46,000
Esketamine (Spravato):
List price: $590-885 per session depending on dose
Induction phase (8 sessions in 4 weeks): $4,720-7,080
Maintenance year (weekly to biweekly): $14,000-23,000
Total first year: $18,000-32,000
Insurance coverage:
IV ketamine: Usually NOT covered (off-label use)
Esketamine: Often covered by insurance after prior authorization demonstrating TRD
Medicare covers esketamine with restrictions
High copays and coinsurance are common even with coverage
The ongoing cost of indefinite weekly maintenance makes ketamine potentially more expensive over time than treatments with lighter maintenance burdens, despite lower upfront costs.
If you're reading this guide, you've likely tried multiple antidepressants without adequate success. The question becomes: is there still a role for medications in your treatment plan?
Even in treatment-resistant depression, medications often remain valuable—just not necessarily as the primary treatment:
1. As continuation therapy after successful brain stimulation: Studies consistently show that continuing antidepressants after achieving remission with TMS, SAINT, or ECT significantly improves durability. You're not relying on the medication to fix your depression, but rather to help maintain the improvements created by brain stimulation.
2. Augmentation strategies: Adding certain medications to boost antidepressant response:
Lithium augmentation: Particularly effective with tricyclic antidepressants
T3 (thyroid hormone): Can enhance response even without thyroid dysfunction
Atypical antipsychotics: Aripiprazole (Abilify), quetiapine (Seroquel), and brexpiprazole (Rexulti) have FDA approval for augmentation in TRD
Stimulants: Sometimes helpful for energy and concentration when used carefully
3. Genetic testing considerations: Pharmacogenomic testing can identify which medications you're most likely to metabolize effectively, potentially explaining past failures and guiding better choices. While not a crystal ball, it can inform medication selection.
4. MAOIs for highly resistant cases: Monoamine oxidase inhibitors (like Nardil or Parnate) are underutilized older antidepressants that can be remarkably effective for treatment-resistant depression. The dietary restrictions and medication interactions make them inconvenient, but for some patients they're life-changing.
The landmark STAR*D trial, which tracked over 4,000 patients through sequential medication trials, revealed sobering statistics about medication-only approaches to TRD:
47% of remitters relapsed within 1 year despite continuing their medication
For those who responded without full remission: 68% relapsed within 1 year
For the most treatment-resistant patients requiring multiple medication switches: only 2.7% maintained stable remission through 12 months
With each failed medication trial, the odds of the next trial working dropped dramatically
Treatment resistance tends to worsen over time with continued unsuccessful medication trials
When you've already failed multiple adequate medication trials, the probability that trial number 5 or 6 will suddenly work is very low. The STAR*D reanalysis found that only 17.8% of patients maintained remission through 12 months across all treatment steps.
Source: STAR*D Long-Term Remission Analysis
You should strongly consider brain stimulation, intensive psychotherapy, or other advanced treatments if you:
Have tried two or more antidepressants at adequate doses for sufficient duration without satisfactory improvement
Experience severe functional impairment—your depression significantly affects your ability to work, maintain relationships, or handle daily responsibilities
Have suicidal ideation that persists despite medication trials
Have been cycling through medications for years without sustained relief
Experience intolerable side effects that limit your ability to take medications at therapeutic doses
Are losing time—months or years of your life passing while trying medication after medication
There's no rule that says you must try every available medication before considering brain stimulation or other approaches. In fact, the evidence suggests that earlier intervention with treatments like TMS or intensive psychotherapy may prevent the progressive worsening that can occur with prolonged treatment resistance.
The most effective approach for many patients combines the strengths of different treatments:
The synergistic effect: Brain stimulation (fMRI Accelerated TMS, standard TMS, or ECT) can rapidly reset dysfunctional neural circuits, while medications help maintain those changes and address different aspects of depression biology. Together, they achieve better outcomes than either alone.
Typical combination strategy:
Begin brain stimulation while continuing current medications (unless contraindicated)
Achieve remission through intensive brain stimulation course
Optimize medication regimen for maintenance—potentially simplifying to reduce side effects
Use early warning signs to trigger brief brain stimulation retreatment if needed
Continue medications for at least 6-12 months minimum
Reducing medication burden: Some patients find that after successful SAINT TMS or ECT, they can reduce the number or doses of medications they take while maintaining wellness. The brain stimulation provides the heavy lifting, with medications playing a supporting role rather than being the primary treatment.
If you're focused on brain stimulation and medications, you might overlook what could be the most durable treatment option: evidence-based psychotherapy specifically designed for treatment-resistant depression. Unlike treatments that provide relief as long as you continue them, therapy aims to build lasting skills and change thought patterns that can protect you even after treatment ends.
Not all therapy is created equal for treatment-resistant depression. Three approaches have the strongest evidence base:
1. Cognitive Behavioral Therapy (CBT) for Treatment-Resistant Depression
CBT helps you identify and change distorted thinking patterns and behaviors that maintain depression. For TRD specifically, the approach is more intensive and prolonged than standard CBT:
The large CoBalT trial from the UK tracked 469 TRD patients receiving CBT plus usual care versus usual care alone
At 46 months (nearly 4 years), CBT recipients maintained significant benefits: 43% response rate compared to controls, with lasting improvements in functioning
The benefits persisted long after the therapy ended—evidence of true durability
Typical course: 12-18 sessions over 3-4 months
Source: CoBalT Long-Term Trial Results
2. Cognitive Behavioral Analysis System of Psychotherapy (CBASP)
Developed specifically for chronic depression, CBASP focuses on how your behaviors affect outcomes and helps you understand the connection between your actions and consequences:
Intensive inpatient CBASP programs showed 84% response and 44% remission rates
At 6-month follow-up, 40% of responders had relapsed, but 48% maintained sustained response at 52 weeks
Particularly effective for those with early childhood trauma or chronic interpersonal difficulties
Typically requires a specialized CBASP-trained therapist
Source: CBASP Inpatient Study
3. Mindfulness-Based Cognitive Therapy (MBCT)
MBCT combines meditation practices with cognitive therapy elements, teaching you to relate differently to depressive thoughts rather than trying to change them:
For TRD specifically, one key study found response rates that improved from 30.3% at 8 weeks to 43.7% at 52 weeks—the benefits consolidated over time rather than fading
Depression symptoms, quality of life, rumination, and mindfulness skills all maintained or improved during the 6-month follow-up period
A 2025 Lancet Psychiatry study showed small-to-medium effect sizes even in patients who hadn't responded to intensive NHS therapy programs
Typical course: 8-week group program with daily home practice
Source: MBCT 6-Month Follow-Up Study
When delivered by trained therapists using evidence-based protocols, these therapies show impressive outcomes:
CBT: 43% maintained response at 4 years in the CoBalT trial
CBASP: 44% remission in intensive programs, 48% sustained response at 1 year
MBCT: 43.7% response at 52 weeks, with consolidation of benefits over time
These may seem modest compared to SAINT's 70-90% remission rate, but remember: therapy's effects can last indefinitely once you've learned the skills, whereas brain stimulation may require ongoing maintenance.
Here's where psychotherapy truly shines—it may provide the most enduring protection against relapse because you're building skills and changing thinking patterns rather than relying on external interventions:
Meta-analyses of CBT for depression show:
31.6% relapse rates versus 41.3% for controls over various timeframes
In the first 12 months after CBT, the risk of new depressive episodes dropped by 76% in some analyses
At time points beyond 12 months, CBT continued showing benefit
Source: CBT Relapse Prevention Meta-Analysis
Psychotherapy vs pharmacotherapy durability: Research directly comparing the two approaches found that "psychotherapy may yield greater durability of treatment gains than pharmacotherapy." When antidepressants are discontinued, relapse rates jump to 74-77%, but after CBT discontinuation, rates are significantly lower.
Source: American Journal of Psychiatry Expert Perspective
The key insight: Unlike medications that stop working when you stop taking them, or brain stimulation that may require maintenance, therapy teaches you skills you can use for life. You become your own therapist in many ways.
The most exciting finding may be that therapy and brain stimulation work synergistically—addressing both the neural circuit dysfunction and the thought/behavior patterns that maintain depression:
The combination advantage:
Brain stimulation can rapidly reduce symptoms, making you more able to engage effectively in therapy
Therapy provides tools to handle stressors and challenges that might otherwise trigger relapse
Together, they may achieve better long-term outcomes than either alone
Some patients find that SAINT or traditional TMS make therapy finally effective after previous therapy attempts didn't help
Optimal sequencing strategies:
Concurrent: Start therapy alongside SAINT/rTMS treatment to immediately build skills while symptoms improve
Sequential: Complete brain stimulation first to achieve remission, then engage in therapy to consolidate gains and prevent relapse
Therapy-first: For less severe TRD, try intensive evidence-based therapy before brain stimulation
There's no single right answer—the best sequence depends on your symptom severity, previous therapy experience, and personal preferences.
Evidence for routine booster therapy sessions is surprisingly mixed:
A 2025 systematic review found no benefit of booster sessions in one large study—over 95% maintained remission at 24 months with or without boosters
This suggests that for some patients, the skills learned provide lasting protection without ongoing appointments
However, monthly maintenance IPT sessions helped 74% remain relapse-free over 2 years in another study
The value may depend on the therapy type, patient characteristics, and life stressors
Many therapists recommend periodic "check-in" sessions (every 2-3 months) rather than formal ongoing weekly therapy, allowing you to troubleshoot emerging difficulties before they become full relapse.
Typical investment:
12-18 sessions over 3-4 months for most evidence-based TRD protocols
Some programs offer more intensive approaches (multiple sessions per week)
Cost per session: $100-300 depending on location and therapist credentials
Total cost: $1,200-5,400 for a full course
Insurance coverage: Most insurance plans cover psychotherapy with varying copays. Mental health parity laws require insurance to cover mental health treatment at rates comparable to medical treatment, though high deductibles can still create barriers.
The time commitment difference: While therapy requires weekly appointments for 3-4 months initially, this may be more manageable than:
6-9 weeks of daily TMS (36-40 appointments)
Weekly ketamine infusions indefinitely
Monthly ECT sessions with anesthesia indefinitely
And unlike those treatments, therapy's benefits don't disappear when you stop—the skills remain.
Getting well is only half the battle—staying well is equally important. Understanding how long each treatment's benefits typically last, and what maintenance is required, should be central to your decision-making.
This section ranks all TRD treatments by their durability, both with and without ongoing maintenance. The differences are striking and may change which treatment you choose.
If you received treatment and then had no follow-up care whatsoever—no maintenance sessions, no medications, nothing—how long would you typically stay well? Here's the hierarchy from best to worst:
The critical insight: Psychotherapy offers the best "maintenance-free" durability because you retain the skills learned. Ketamine shows the poorest durability—benefits evaporate within weeks of stopping. Every other treatment falls somewhere in between.
When proper continuation treatment is provided—whether that's maintenance brain stimulation, ongoing medications, booster therapy, or combinations—the durability picture transforms dramatically:
The game-changing finding: SAINT with personalized maintenance achieved 100% sustained remission at 12 months—though this requires independent replication. What makes this remarkable is the light maintenance burden: an average of just 14.9 days of treatment over the entire year, with most retreatment courses requiring only 1-2 days.
Compare to the alternatives:
Ketamine: 52 clinic visits per year (weekly infusions)
Standard TMS: 12-24 clinic visits per year (monthly/biweekly sessions)
ECT: 12 sessions per year with anesthesia (monthly treatments)
SAINT: 3-4 treatment episodes averaging 15 days total per year
The ability to achieve sustained remission with minimal maintenance represents a potential breakthrough in long-term TRD management.
No statistic captures everyone's experience. Several factors influence how long YOUR benefits will last:
Factors associated with better durability:
Achieving full remission (not just response) with initial treatment
Lower number of previous failed treatments
Absence of chronic stressors (ongoing life difficulties)
Strong social support system
Good compliance with continuation treatment plans
Addressing comorbid conditions (anxiety, substance use, medical issues)
Engaging in psychotherapy alongside biological treatments
Factors associated with earlier relapse:
Residual symptoms after treatment (incomplete remission)
High degree of treatment resistance (many failed treatments)
Comorbid personality disorders or trauma history
Ongoing severe stressors or interpersonal difficulties
Poor medication compliance or premature discontinuation
Lack of follow-up care or monitoring
Your treatment team should help you identify your specific risk factors and build a maintenance plan that accounts for them.
Beyond just "does it work?", consider the real-world commitment required to maintain wellness:
Comparing Time Commitment Over 1 Year:
This time analysis doesn't account for the psychological burden—daily pills feel different from monthly appointments, which feel different from intensive multi-day retreatment courses. Consider which maintenance pattern fits best with your life, personality, and preferences.
Understanding the true cost of each treatment requires looking beyond the upfront price tag to the total investment over 1-2 years, including maintenance. The cheapest initial option may not be the most cost-effective over time.
Surprising findings from this cost analysis:
Ketamine may be the most expensive option long-term due to indefinite weekly maintenance, despite lower upfront costs
SAINT becomes more cost-competitive over time as retreatments require less than the initial course and happen only quarterly
The cheapest options (continued antidepressants) may cost more over years when they don't work—lost productivity, additional treatments, and continued suffering
Psychotherapy may be the most cost-effective option for those who respond, given its durability without ongoing treatment costs
Healthcare economists use a measure called "quality-adjusted life years" (QALYs) to compare treatment value. While QALY analyses for SAINT aren't yet available, consider these factors:
Direct medical costs are only part of the picture:
Lost productivity: Treatment-resistant depression can cost $10,000-20,000+ per year in lost work productivity
Relationship impacts: Divorce, family strain, and social isolation carry significant personal and financial costs
Additional healthcare utilization: Emergency room visits, hospitalizations, and comorbid medical conditions add substantial costs
Quality of life: How much is it worth to have your life back months or years sooner?
The speed-to-relief factor: If SAINT gets you well in 5 days versus 6-9 weeks for standard TMS, that's 1-2 months of your life you get back—time you can't put a price on.
The durability factor: Treatments requiring less intensive maintenance (SAINT quarterly vs ketamine weekly) reduce not just financial costs but also time costs, schedule disruption, and psychological burden of ongoing appointments.
Medicare Coverage (as of July 2025):
SAINT: Covered at $19,703
Standard TMS: Covered
ECT: Covered
Esketamine: Covered with restrictions
Private Insurance:
Standard TMS: Usually covered after documented medication failures
ECT: Generally well-covered
Esketamine: Coverage improving but requires prior authorization
SAINT: Limited coverage currently; case-by-case appeals may succeed
IV Ketamine: Usually not covered (off-label use)
Psychotherapy: Covered with copays; parity laws apply
Financial Assistance Options:
Payment plans: Most clinics offer plans to spread costs over 6-12 months
Research trials: Opportunity for reduced-cost or free treatment while contributing to science
Financial assistance programs: Many clinics have sliding scale or charity care programs
Insurance appeals: Some SAINT clinics provide support for appealing insurance denials
Health Savings Accounts (HSAs) and Flexible Spending Accounts (FSAs): Can be used for most treatments
With so many options, how do you decide which treatment—or combination of treatments—is right for you? The answer depends on multiple factors unique to your situation.
1. Severity and Urgency
Mild-moderate TRD: Consider psychotherapy or standard TMS first
Severe TRD with significant functional impairment: SAINT, ECT, or ketamine for rapid relief
Suicidal crisis or severe psychotic features: ECT or esketamine (FDA-approved for suicidal ideation)
Chronic but stable TRD: Time for thoughtful therapy or gradual TMS approach
2. Previous Treatment History
Failed 1-2 medications: Standard TMS or intensive therapy may be sufficient
Failed 4+ medications: Consider SAINT, ECT, or ketamine
Failed standard TMS: SAINT or ECT are logical next steps
Never had adequate therapy: Try evidence-based psychotherapy before more invasive options
3. Functional Impairment Level
Can't work or function: Need fastest relief possible (SAINT, ECT, or ketamine)
Functioning but struggling: Can accommodate 6-9 week standard TMS protocol or 3-4 month therapy
Need to maintain work: Consider intensive options that minimize time away (5-day SAINT vs 6-9 week daily TMS)
4. Available Time for Treatment
Can take a week off: SAINT is ideal
Can accommodate daily appointments for 6-9 weeks: Standard TMS
Can commit to weekly sessions for 3-4 months: Psychotherapy
Need ongoing weekly commitment: Ketamine may fit your schedule
5. Financial Considerations
Good insurance, limited cash: Standard TMS or ECT (well-covered)
Medicare eligible: SAINT coverage begins July 2025
High cash resources: SAINT may be most cost-effective over time
Limited resources: Psychotherapy may offer best value if effective
6. Access to Specialized Centers
Near a SAINT-capable center: Worth serious consideration
No SAINT access: Standard TMS widely available
Rural location: Telemedicine therapy options expanding
7. Personal Preferences and Values
Want to avoid medications: SAINT or ECT can work without antidepressants (though maintenance medications help)
Want to build lasting skills: Psychotherapy offers unique long-term value
Uncomfortable with anesthesia: SAINT or TMS rather than ECT
Prefer gradual change: Standard TMS or therapy rather than intensive protocols
Here's a practical framework for choosing your next step based on common scenarios:
SCENARIO 1: You've failed 2-3 antidepressants, moderate depression, never had good therapy
Recommended path: Intensive evidence-based psychotherapy (CBT, CBASP, or MBCT) with specialist therapist. Consider adding or continuing medications. Reserve brain stimulation if therapy proves insufficient.
Why: Many "treatment-resistant" patients never received adequate, evidence-based therapy. The durability and skill-building of therapy make it worth trying before more invasive options.
SCENARIO 2: Severe depression, failed 4+ medications, significant functional impairment, can access SAINT TMS
Recommended path: SAINT TMS for rapid remission, continue or optimize medications for maintenance, add therapy during or after SAINT to build long-term resilience.
Why: High treatment resistance + severe impairment + need for speed = SAINT is ideal. The 70-90% remission rate and 3-day average time to relief address your urgent needs, while combination approach maximizes durability.
SCENARIO 3: Moderate-severe depression, failed multiple medications, standard TMS didn't work, can't access SAINT
Recommended path: ECT with comprehensive continuation plan (C-ECT + medications), or ketamine for rapid relief followed by transition to maintenance protocol.
Why: When SAINT isn't accessible and standard TMS failed, ECT and ketamine are your remaining rapid-relief options. ECT has longer durability with proper maintenance; ketamine works fastest but requires indefinite continuation.
SCENARIO 4: Chronic depression for years, failed many treatments, functioning but suffering, no urgent crisis
Recommended path: Comprehensive evaluation at specialized TRD center. Consider CBASP intensive program or combination of SAINT + ongoing CBASP/CBT for best long-term outcomes.
Why: Chronic, highly resistant depression without crisis allows time for thorough evaluation and optimal treatment sequencing. Combination approaches achieve best sustained remission for the most resistant cases.
SCENARIO 5: Active suicidal ideation, severe depression, immediate danger
Recommended path: Hospitalization if needed for safety, then ECT (fastest for severe/suicidal depression) or esketamine (FDA-approved for suicidal ideation). SAINT can be considered but has less evidence for immediate crisis management.
Why: Safety comes first. ECT has decades of evidence for severe, suicidal depression. Esketamine's rapid onset and FDA indication make it appropriate. After crisis stabilization, transition to optimal maintenance.
For many patients with treatment-resistant depression, the best outcomes come from combining treatments that work through different mechanisms:
Why combination approaches work better:
Depression involves multiple dysfunctional systems—neural circuits, neurotransmitters, thought patterns, behaviors, interpersonal relationships
No single treatment addresses all these factors
Brain stimulation + psychotherapy + optimized medications may produce synergistic effects
Treating both the biology AND the psychology creates more robust, lasting change
Example effective combinations:
1. SAINT + Continued Medications + CBT/CBASP:
SAINT rapidly resets dysfunctional neural circuits (5 days)
Medications help maintain those changes
Therapy builds skills to handle stress, challenge distorted thinking, improve relationships
Brief SAINT retreatment when early warning signs appear
Outcome: The 100% sustained remission study used this type of protocol
2. Intensive CBASP + Medication Optimization + Maintenance TMS as needed:
CBASP addresses chronic interpersonal patterns and learned helplessness
Medications provide neurochemical support
Maintenance TMS if symptoms worsen despite therapy and medications
Outcome: Good long-term durability with skills-based protection against relapse
3. ECT for Rapid Stabilization + Transition to SAINT Maintenance + Ongoing Therapy:
ECT for fastest relief in crisis
Transition to quarterly SAINT retreatments (lighter burden than monthly C-ECT)
Therapy to address underlying patterns
Outcome: Rapid crisis resolution with more sustainable long-term management
Sequencing considerations:
Concurrent: Start all treatments at once—often ideal for maximum synergy
Sequential: Brain stimulation first to achieve remission, then therapy to consolidate—works well when depression is too severe for effective therapy engagement
Layered: Begin with most urgent need, add others as you stabilize—practical when resources or access are limited
When evaluating your options with healthcare providers, these questions can help you make an informed decision:
"Based on my specific treatment history, which option offers the highest probability of remission?"
"What does 'maintenance' actually look like for each treatment—how often, for how long, at what cost?"
"If this treatment doesn't work, what would be the next logical step?"
"Have I had an adequate trial of evidence-based psychotherapy with a specialist before pursuing brain stimulation?"
"What factors in my case make you recommend this particular treatment over the alternatives?"
"Can we combine treatments—like therapy alongside brain stimulation—for better outcomes?"
"What does the research say about long-term durability for my specific situation?"
"How will we know if treatment is working, and when should we change course if it isn't?"
"What will the maintenance plan be if treatment is successful?"
"Are there financial assistance options or payment plans available?"
When to get a second opinion:
You're being pushed toward a specific treatment without clear rationale
The provider doesn't seem familiar with newer options like SAINT
You're uncomfortable with the recommended approach
You've been told "nothing else can be done"
The treatment plan doesn't include a clear maintenance strategy
Working with a specialist in treatment-resistant depression—rather than a general psychiatrist—often yields better treatment matching and outcomes for highly resistant cases.
At Cognitive FX, we understand that getting the right treatment for treatment-resistant depression isn't just about having access to advanced technology—it's about personalized care, comprehensive evaluation, and a team that won't give up on finding what works for you.
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Advanced fMRI brain imaging capabilities: We map YOUR unique brain networks to provide truly personalized treatment targeting
Integration of brain stimulation with psychotherapy: Our multidisciplinary team coordinates care so you benefit from both neural circuit changes and skill-building
Personalized maintenance protocols: We check in regularly to determine if and when you need retreatment, minimizing maintenance burden while maximizing sustained remission
Outcomes tracking: We monitor your progress with validated scales and adjust treatment based on data, not guesswork
Comprehensive assessment process: We don't just ask about your medication trials. We conduct thorough evaluation of your complete treatment history, symptom patterns, functional impairments, and treatment goals to match you with the optimal approach.
Multiple treatment modalities under one roof: Whether you need SAINT-style TMS, standard TMS, intensive psychotherapy, or combinations of approaches, we provide coordinated care without referring you elsewhere.
Coordination between specialists: Our psychologist, brain stimulation team, and treatment director communicate regularly about your progress and adjust the treatment plan collaboratively.
Ongoing support and monitoring: You're not on your own after initial treatment. We provide structured follow-up and rapid access to retreatment when needed.
Financial counseling and insurance navigation: Our patient coordinators help you understand costs, explore financial assistance options, and navigate insurance appeals when appropriate.
Treatment-resistant depression requires specialized expertise and access to the most advanced treatments available. At Cognitive FX, we've invested in both—because we believe every patient deserves comprehensive options and excellent care.
If you've read this far, you're taking an important step—educating yourself about all available options rather than accepting that depression is something you just have to live with. That decision to keep searching for answers is what separates people who eventually achieve wellness from those who give up.
The evidence is clear: effective treatments for treatment-resistant depression exist. Whether it's fMRI-guided TMS with its unprecedented 70-90% remission rates, ECT's power for severe cases, ketamine's rapid relief, evidence-based psychotherapy's skill-building and durability, or—most often—combinations of these approaches, you have options beyond trying yet another medication.
The next step is a comprehensive evaluation with a specialist in treatment-resistant depression who understands the full range of options and can help you navigate to the treatment most likely to work for your specific situation. Most patients can begin advanced treatment within 2-4 weeks of initial consultation.
Schedule your free consultation here:
Don't wait years hoping the next medication will be different. The research shows that with each failed treatment, the next one becomes less likely to work, and treatment resistance can worsen over time. Early intervention with advanced treatments may prevent progressive worsening and get you back to your life sooner.
For further support and information:
National Alliance on Mental Illness (NAMI): www.nami.org - Support groups, education, advocacy
Depression and Bipolar Support Alliance (DBSA): www.dbsalliance.org - Peer-led support groups
Stanford Neuromodulation Therapy Research: Stanford Medicine Brain Stimulation Lab
FDA TMS Information: FDA Neurological Devices - TMS
National Institute of Mental Health: NIMH Depression Information
This comprehensive analysis draws on peer-reviewed research published in leading medical journals. All sources are directly linked throughout the article and compiled here for verification:
SAINT/SNT Primary Studies:
Antidepressants & Standard TMS:
ECT:
Ketamine/Esketamine:
Psychotherapy:
DISCLAIMER: SAINT™ is a trademark of The Board of Trustees of the Leland Stanford Junior University (“Stanford”) and has exclusively licensed such mark to Magnus Medical. Cognitive FX is neither endorsed by Stanford nor utilizes Magnus Medical equipment nor claims to be offering the SAINT protocol as prescribed by Stanford University et. al. or Magnus Medical. We provide fMRI guided intermittent theta burst TMS with target locations determined by fMRI and our prescribing physician.
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