After trying three or four different antidepressants without adequate relief, many people assume they’ve exhausted their treatment options and just need to accept living with persistent depression. Research analyzing 69 randomized controlled trials involving more than 10,000 participants identified six treatments with significantly higher response rates than placebo for treatment-resistant depression: electroconvulsive therapy, TMS, ketamine, esketamine, theta-burst stimulation, and minocycline (Saelens et al., 2024). Understanding what these advanced options are, how they compare, and which might be right for you can open doors you didn’t know existed.
Why Standard Treatments Sometimes Aren’t Enough
Depression involves complex interactions between neurotransmitters, neural circuits, inflammation, hormones, and psychological factors. Standard antidepressants primarily target serotonin and norepinephrine, which helps many people but leaves about 30% without adequate improvement even after multiple medication trials.
When depression doesn’t respond to standard treatments, it’s called treatment-resistant depression. This doesn’t mean your depression is untreatable—it means the first-line approaches haven’t worked for your particular biology and circumstances. The cumulative remission rate across multiple treatment steps is around 67%, but relapse rates increase significantly for people who require more treatment attempts (Innovative Approaches in TRD, 2024).
At H3O Wellness, we see patients from across southern Idaho who’ve been told by previous providers that they’ve tried everything available. Often, they haven’t actually tried the advanced interventions that work through different mechanisms than standard antidepressants. Our psychiatric services team has more than 75 years of combined healthcare experience specifically with treatment-resistant cases, and we’ve seen how transformative these specialized treatments can be.
TMS: Non-Invasive Brain Stimulation
Transcranial magnetic stimulation uses focused magnetic pulses to stimulate underactive brain regions involved in depression. We covered TMS in detail in our February blog, but here’s how it compares to other advanced options.
TMS requires the biggest time commitment—daily sessions for approximately six weeks. However, it produces no systemic side effects since it’s localized brain stimulation rather than a medication affecting your whole body. You remain fully awake during treatment, can drive yourself to and from appointments, and return immediately to normal activities afterward.
Research shows that 50–60% of people with treatment-resistant depression respond to TMS, with 30–40% achieving remission, meaning their symptoms resolve to subclinical levels. Real-world data suggests even higher effectiveness rates, with some studies showing improvement in up to 83% of patients (UTHealth Houston, 2025). The benefits often persist for a year or longer, though some people eventually need retreatment.
TMS is covered by Medicare and many insurance plans when criteria are met. At H3O Wellness, we’re the only TMS therapy provider within 120 miles, using the NeuroStar system. The treatment works best for major depressive disorder that hasn’t responded to medications, particularly for people who want to avoid adding more medications or who’ve experienced intolerable side effects from drugs.
SPRAVATO®: Rapid-Acting Nasal Spray
SPRAVATO® (esketamine) is an FDA-approved nasal spray that works through the glutamate system rather than serotonin. It’s specifically approved for treatment-resistant depression and can now be used as monotherapy without requiring an oral antidepressant.
The treatment schedule is more intensive initially than TMS—twice weekly for four weeks, then tapering based on response. However, each session is shorter. You self-administer the nasal spray at our office, then stay for two hours of monitoring before being driven home. You cannot drive after treatment due to dissociative effects and potential sedation.
Clinical trials showed that 22.5% of patients achieved remission after four weeks with SPRAVATO® compared to 7.6% with placebo, with some patients experiencing improvement within 24 hours (Johnson & Johnson, 2025). This rapid onset makes it particularly valuable for severe depression or when quick relief is important.
SPRAVATO® is covered by most major insurance plans when medical criteria are met. We’re the only certified SPRAVATO® treatment provider within 150 miles, serving patients throughout the Magic Valley region. The treatment works best for adults with treatment-resistant depression who need rapid symptom relief and are comfortable with the monitoring requirements.
Ketamine: Flexible Treatment Options
Traditional ketamine therapy offers both IV and intramuscular administration options. Unlike SPRAVATO®, which is FDA-approved but restricted to certified centers, ketamine has been used off-label for depression for years and provides more flexibility in dosing and administration routes.
IV ketamine infusions typically last about 40 minutes, with patients resting in our office for the full session. IM ketamine involves a quick injection followed by monitoring. Both routes produce rapid effects, often within hours or days. Treatment protocols usually involve 6–8 sessions over 2–3 weeks initially, followed by maintenance sessions as needed.
Research shows significant antidepressant effects with ketamine for treatment-resistant cases. A network meta-analysis found ketamine among the treatments demonstrating higher response rates versus placebo (Saelens et al., 2024). Some patients respond better to IV ketamine while others prefer IM administration—we can adjust based on your individual response.
Ketamine is typically not covered by insurance when used for depression, though some plans may cover it in certain situations. The flexibility in dosing and administration makes it valuable for patients who need options that SPRAVATO®’s fixed protocol doesn’t provide. We also offer ketamine-assisted psychotherapy, combining the neuroplastic effects with therapeutic work for a more comprehensive treatment experience.
How These Treatments Compare
Each advanced treatment has distinct advantages and considerations. TMS requires the longest time commitment but produces no systemic side effects and you can drive yourself. SPRAVATO® offers rapid onset and FDA approval but requires transportation and intensive monitoring. Ketamine provides dosing flexibility but typically lacks insurance coverage.
Regarding effectiveness, a comprehensive analysis found that electroconvulsive therapy showed the highest response rates among all treatments, followed by various forms of brain stimulation and glutamatergic treatments. The network meta-analysis comparing 25 different treatments found that TMS, ketamine, and esketamine all demonstrated significantly higher response rates than placebo (Saelens et al., 2024).
Response rates don’t tell the whole story, though. Some people respond dramatically to one treatment while not responding to another. This individual variability means the “best” treatment is the one that works for your specific biology and circumstances. Results vary by individual, and sometimes finding the right approach involves trying more than one advanced option.
Combination and Sequential Approaches
Many patients achieve best outcomes by combining treatments that address depression through different mechanisms. For instance, using TMS to normalize neural circuit function while continuing an optimized medication regimen often produces better results than either alone.
Sequential approaches can also be effective. Some patients use SPRAVATO® or ketamine to achieve rapid improvement, then transition to TMS for longer-lasting benefits. Others start with TMS and add ketamine if they respond partially but need additional improvement. At H3O Wellness, we can coordinate these different modalities because we offer all of them.
Research on combination approaches is still developing, but early evidence suggests synergistic effects. For example, combining ketamine’s neuroplastic priming effects with TMS’s targeted circuit stimulation may enhance response rates and shorten treatment timelines (Ketamine and Esketamine in Psychiatry, 2025).
The key is thoughtful sequencing based on your specific situation. Severe symptoms might call for rapid-acting treatments first. Chronic, stable depression might benefit from starting with the most durable option. Your treatment history, previous responses, practical constraints, and preferences all factor into the optimal approach. Our ketamine for depression service page outlines how we tailor these protocols for each patient.
What to Consider When Choosing
Several factors should inform your decision about which advanced treatment to pursue. Time commitment matters—can you make daily appointments for six weeks for TMS, or would the less frequent but more intensive SPRAVATO® schedule work better? Transportation is another consideration since you can drive yourself for TMS but need rides for SPRAVATO® or ketamine.
Insurance coverage significantly affects out-of-pocket costs. TMS is widely covered, SPRAVATO® is often covered, and ketamine typically isn’t. However, even paying out of pocket for ketamine might be worth it if it works when nothing else has. We accept 15 major insurance carriers at H3O Wellness and can help you verify coverage for different options on our insurance information page.
Side effect profiles vary considerably. TMS produces minimal side effects—maybe temporary scalp discomfort or headaches. SPRAVATO® and ketamine cause temporary dissociation and require monitoring. If you have cardiovascular issues, blood pressure effects from ketamine or esketamine become more concerning. We evaluate your complete medical history to ensure any treatment we recommend is safe for you.
Previous treatment responses provide clues about what might work. If you’ve responded partially to antidepressants but not fully, augmentation with TMS might push you into remission. If you haven’t responded at all to serotonergic medications, glutamatergic treatments like SPRAVATO® or ketamine that work through entirely different mechanisms might be more promising.
The Reality of Treatment-Resistant Depression in Rural Idaho
Living in southern Idaho creates geographic barriers to accessing advanced depression treatments. Many specialized interventions are only available in major metropolitan areas, requiring patients to travel to Boise, Salt Lake City, or beyond for care. This distance becomes prohibitive when treatments require frequent appointments.
We’ve specifically structured our services at H3O Wellness to address these access gaps. We’re the only providers of both TMS and SPRAVATO® within significant distances—120 miles for TMS and 150 miles for SPRAVATO®. Our locations in Twin Falls and Burley help minimize travel for patients coming from different parts of the Magic Valley region.
Extended hours, Monday through Friday from 10 AM to 8 PM, accommodate various work schedules. For treatments requiring frequent visits, some patients coordinate schedules to make the travel manageable. Others temporarily stay with family or friends in the area during intensive treatment phases. We work with patients to find solutions that make advanced treatment accessible despite the geographic challenges. For more on what our patients experience, visit our patient testimonials page.
When to Consider Advanced Treatments
You should consider advanced treatments if you’ve tried at least two different antidepressants at adequate doses for sufficient duration without adequate improvement. This doesn’t mean you need to have tried every possible medication—treatment-resistant depression is defined as failure to respond to at least two trials, and further medication trials show diminishing returns.
Severe functional impairment makes advanced treatment more urgent. If your depression prevents you from working, maintaining relationships, or performing basic self-care, waiting months to try yet another antidepressant might not be the right approach. Advanced treatments offering rapid onset or higher response rates deserve consideration.
Intolerable medication side effects are another reason to pursue non-medication or alternative options. If standard antidepressants cause weight gain, sexual dysfunction, or other unacceptable effects, TMS provides a completely different approach. Even SPRAVATO® and ketamine, while they affect the brain, work through different mechanisms with different side effect profiles.
The presence of suicidal thoughts increases urgency. Rapid-acting treatments like SPRAVATO® or ketamine can provide quicker relief than waiting weeks for another antidepressant to work. SPRAVATO® is specifically FDA-approved for depression with acute suicidal ideation. We take safety seriously and conduct thorough risk assessments to determine the most appropriate intervention. You can learn more about this on our ketamine for suicidal ideation service page.
What the Research Says About Long-Term Outcomes
Long-term effectiveness varies by treatment. TMS benefits often persist for a year or longer, with the option to repeat treatment if symptoms return. Repeated TMS courses remain effective, which is valuable for people who need periodic maintenance.
SPRAVATO® and ketamine typically require ongoing treatment to maintain benefits. After the initial improvement, many patients transition to maintenance schedules with less frequent sessions. Some people maintain gains with monthly treatments, while others need more frequent maintenance. The requirement for ongoing treatment isn’t necessarily negative—it’s similar to how many people take antidepressants long-term.
Research tracking patients over time shows that people who respond to advanced treatments often maintain significantly better functioning than their pre-treatment baseline, even if they need periodic maintenance. The quality of life improvements—being able to work, engage in relationships, and function independently—make ongoing maintenance worthwhile for many patients.
A Mayo Clinic expert panel examining next-step options for treatment-resistant depression emphasized the importance of comprehensive evaluation and access to multiple treatment modalities. No single treatment works for everyone, and having options allows for personalized approaches based on individual response patterns (Psychiatrist.com, 2025). For a closer look at how our patients have fared, explore our post on ketamine treatment in Twin Falls, ID.
Making Your Decision
Choosing between advanced treatments isn’t always straightforward. The “best” option depends on your specific circumstances, and sometimes the right choice only becomes clear through discussion with knowledgeable providers who can evaluate your complete situation.
At H3O Wellness, we conduct thorough evaluations that consider your depression severity, treatment history, medical conditions, practical constraints, and preferences. We discuss realistic expectations for each treatment option, including response rates, time commitments, side effects, and costs. This comprehensive approach helps you make informed decisions rather than just guessing which treatment to try. Ready to explore your options? Schedule a consultation with our team — H3O Wellness offers TMS, SPRAVATO®, and ketamine therapy backed by 75 years of combined expertise. Call 208-207-9422 to get started.
FAQ
Q: If I try TMS and it doesn’t work, can I then try SPRAVATO® or ketamine?
A: Yes, absolutely. Different treatments work through different mechanisms, so trying one doesn’t prevent you from trying others. In fact, systematic exploration of different advanced options is standard practice for treatment-resistant depression. We can help you plan an appropriate sequence based on your response to each intervention.
Q: Can I do TMS and ketamine at the same time?
A: Potentially, yes, though this should be carefully coordinated. Some research suggests combining treatments that work through different mechanisms may enhance effectiveness. We’d need to evaluate whether simultaneous treatment is appropriate for your specific situation, but combining approaches is an option we can discuss.
Q: How do I know which treatment is most likely to work for me?
A: There’s no definitive test that predicts individual response, but we use your treatment history, symptom pattern, and other factors to make informed recommendations. Someone who hasn’t responded at all to serotonergic medications might be more likely to benefit from glutamatergic treatments like SPRAVATO® or ketamine. Someone who responded partially might do well with TMS augmentation. We discuss these considerations during evaluation.
Q: Are these treatments just for extremely severe depression?
A: No, they’re appropriate for treatment-resistant depression of varying severity levels. You don’t need to be non-functional or suicidal to pursue advanced treatments. If you’ve tried multiple standard approaches without adequate improvement and depression is affecting your quality of life, these options deserve consideration regardless of whether your depression qualifies as “severe” on clinical scales.
Q: Will insurance cover multiple advanced treatments if the first one doesn’t work?
A: Coverage varies by insurance plan and treatment. Some plans will cover sequential attempts at different treatments, while others have more restrictive policies. We can help you understand your specific coverage and work with your insurance company to advocate for appropriate care when multiple approaches are needed.
Moving Forward With Treatment-Resistant Depression
Living with depression that hasn’t responded to standard treatments is exhausting and discouraging, but you haven’t exhausted your options just because typical antidepressants haven’t worked. Advanced treatments with different mechanisms, higher response rates, and specific benefits for resistant cases provide genuine hope backed by solid research.
The key is connecting with providers who have expertise in these specialized interventions and can help you determine which approach makes sense for your situation. Not every patient responds to every treatment, but with multiple advanced options available, most people with treatment-resistant depression can find meaningful improvement.
References
Saelens, J., Gramser, A., Watzal, V., et al. (2024). Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis. Nature Neuropsychopharmacology. https://www.nature.com/articles/s41386-024-02044-5
Psychiatrist.com. (2025). Next-Step Treatment Options for Treatment-Resistant Depression: Insights From the Mayo Clinic Depression Center Panel. https://www.psychiatrist.com/jcp/next-step-options-treatment-resistant-depression-mayo-clinic-depression-center-panel/
Innovative approaches in the treatment-resistant depression: exploring different therapeutic pathways. (2024). PMC – National Library of Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC12397026/
Ketamine and Esketamine in Psychiatry: A Comparative Review Emphasizing Neuroplasticity and Clinical Applications. (2025). MDPI. https://www.mdpi.com/2813-1851/4/3/20
UTHealth Houston. (2025). A New Consensus on Transcranial Magnetic Stimulation (TMS). https://med.uth.edu/psychiatry/2025/04/21/a-new-consensus-on-transcranial-magnetic-stimulation-tms/
Johnson & Johnson. (2025). SPRAVATO® (esketamine) approved as monotherapy for treatment-resistant depression. https://www.jnj.com/media-center/press-releases/spravato-esketamine-approved-in-the-u-s-as-the-first-and-only-monotherapy-for-adults-with-treatment-resistant-depression