Ketamine, TMS, and Spravato: Your Options When Antidepressants Haven't Worked

If you've tried two or more antidepressants and still don't feel better, you're not failing treatment. You have treatment-resistant depression (TRD) — a recognized clinical diagnosis affecting roughly 30% of people with major depressive disorder. This is not a dead end. The options for treatment-resistant depression have expanded dramatically, and 2026 looks different from even five years ago. **What Treatment-Resistant Depression Actually Means** Clinically, TRD is defined as depression that has not responded adequately to at least two different antidepressants taken at therapeutic doses for an adequate duration (typically 6–8 weeks each). This is a common scenario — not a rare edge case. Before assuming you have TRD, a psychiatrist will review whether previous medications were truly optimized: right dose, right duration, right diagnosis. Sometimes what looks like treatment resistance is actually undertreatment or a missed co-occurring condition (like bipolar disorder, ADHD, or thyroid dysfunction). A thorough evaluation is the starting point. **Ketamine Therapy** Ketamine is the most significant advance in depression treatment in decades. Unlike traditional antidepressants that work on serotonin or norepinephrine systems and take weeks to show effect, ketamine acts on glutamate receptors and can produce antidepressant effects within hours to days. IV ketamine infusions are administered in specialized clinics. A typical protocol involves 6 infusions over 2–3 weeks, followed by maintenance infusions as needed. Response rates in TRD are high — approximately 50–70% of patients who haven't responded to multiple antidepressants show meaningful improvement. Ketamine is not without risks. Dissociative effects during infusion are common. It requires careful monitoring. It's not appropriate for everyone. And it's expensive — IV ketamine is rarely covered by insurance, with costs running $400–$800 per infusion. **Spravato (Esketamine)** Spravato is a nasal spray version of esketamine (a component of ketamine) that received FDA approval for treatment-resistant depression in 2019 and for major depressive disorder with suicidal ideation. It's the only ketamine-based treatment with FDA approval specifically for TRD. Unlike IV ketamine, Spravato is sometimes covered by insurance — it has an FDA indication, which many plans recognize. It must be administered in a certified healthcare provider's office with monitoring for at least 2 hours afterward due to dissociation risk. The clinical response profile is similar to IV ketamine: faster onset than traditional antidepressants, meaningful response rates in patients who haven't responded to standard treatments. It's taken twice weekly for 4 weeks initially, then weekly or biweekly for maintenance. **TMS (Transcranial Magnetic Stimulation)** TMS uses focused magnetic pulses to stimulate specific regions of the brain involved in mood regulation — primarily the left dorsolateral prefrontal cortex, which shows reduced activity in depression. TMS is non-invasive. There's no anesthesia, no seizure risk (unlike ECT), and no systemic side effects. Sessions are typically 20–40 minutes, 5 days a week, for 4–6 weeks. The main side effect is mild scalp discomfort or headache during sessions. TMS has FDA clearance for major depressive disorder and is increasingly covered by insurance after failure of one or more antidepressants. Response rates are moderate — approximately 50–60% experience response and 30–35% achieve remission. Newer TMS protocols are improving outcomes. Deep TMS (dTMS) and accelerated TMS protocols (multiple sessions per day, shortening the total treatment course) are showing promising results and are increasingly available. **ECT (Electroconvulsive Therapy)** ECT carries enormous stigma from its historical use, but modern ECT bears little resemblance to its depiction in films. Administered under general anesthesia with muscle relaxants, contemporary ECT is the most effective treatment for severe TRD — with response rates exceeding 70–80%. ECT is typically reserved for severe, life-threatening depression or cases where other interventions have failed. Memory effects (temporary confusion, some short-term memory gaps) are the primary concern, and they are significantly reduced with modern techniques. **What a TRD Evaluation Looks Like** If you're pursuing treatment-resistant depression evaluation, a psychiatrist will: - Review your full medication history (what you've taken, doses, duration, response, side effects) - Assess for co-occurring conditions that may be complicating treatment - Consider augmentation strategies (adding a second medication to your current antidepressant) - Discuss referral pathways for ketamine, Spravato, or TMS This can begin via telehealth. A board-certified psychiatrist can conduct the evaluation, optimize your current medication regimen, and coordinate referral to specialized treatment if appropriate. **The Most Important Thing to Know** Treatment-resistant depression is not untreatable depression. It's depression that requires more than a first-line antidepressant. The options are real, the evidence is solid, and more people are achieving remission from previously treatment-resistant depression in 2026 than at any point in history. If you've been told — or told yourself — that nothing works for your depression, that conclusion may be premature. A fresh evaluation with a psychiatrist who specializes in difficult-to-treat cases is worth pursuing.