What If Neither SPRAVATO Nor TMS Works for Me?

You did everything they asked. You sat through the SPRAVATO sessions in the chair by the window. You drove yourself to thirty-six TMS appointments and learned to recognize the woodpecker tap on your scalp. And then, somewhere around week six or week eight, you noticed the thing you were dreading: nothing was different. The fog had not lifted. The mornings still felt the same. You started to wonder if you were the patient nobody talks about — the one for whom the algorithm just runs out.

You are not that patient. There is no such patient. There is a longer page of options than your prescriber has shown you, and a real chance that one of the next few moves will be the one that works.

What “neither one worked” actually tells us

Treatment-resistant depression has a definition the FDA and the European Medicines Agency both use: depression that has failed to respond to at least two adequate trials of antidepressants of different classes, taken at the right dose, for the right length of time, with the patient actually taking them [1]. Roughly one in three adults with major depression meets that bar [2]. SPRAVATO and TMS sit one tier above that — they are the FDA-approved next steps when standard antidepressants stop working.

Failing both of them is not failing the algorithm. It is finishing the second tier of a much larger one. The honest clinical reality is that depression is not a single disease with a single circuit. It is a final common pathway that several different problems can produce, and the right next step depends on which of those problems is actually driving yours.

Before we get to options, there is a question your prescriber should be asking, and most do not.

The diagnostic tune-up that should happen first

When two evidence-based treatments fail in sequence, the first move is not always a third treatment. Sometimes it is a second look at the diagnosis. The literature on dual non-response is full of patients whose problem turned out to be slightly different from what was being treated. A short list of the things worth re-checking on a Tuesday afternoon:

• Bipolar II that was never caught. Hypomanic episodes can be brief, productive, and easy to forget. If they were not asked about specifically — with examples — they may not have made it into the chart. Antidepressant-only treatment of bipolar depression often looks like treatment failure.
• Untreated ADHD. Particularly in women diagnosed in adulthood, ADHD that gets called “depression” responds poorly to antidepressants and well to stimulant treatment combined with appropriate behavioral support.
• Sleep architecture. Untreated obstructive sleep apnea looks remarkably like treatment-resistant depression and is increasingly common in the demographic getting diagnosed with TRD.
• Trauma that the antidepressant cannot reach. Persistent depressive symptoms in the context of unprocessed trauma frequently need a trauma-focused therapy (EMDR, prolonged exposure, CPT) layered on top of medication.
• Thyroid, B12, iron, and inflammation. A subclinical hypothyroid state, low ferritin, or active autoimmune disease can mimic and aggravate depression. These are worth a basic lab review, not a presumption.
• Medication that is doing nothing because of how you metabolize it. Pharmacogenomic testing is not a magic decoder, but for patients who have failed several antidepressants the modest signal in the PRIME-Care trial — about a 2.8 percentage-point absolute increase in remission at 24 weeks — is worth the lab visit if your insurance covers it [3].

This is the first thing to do, not the last. A diagnostic tune-up frequently surfaces the reason the first two treatments did not land.

Augmentation: oral options that are not TMS or Spravato

If the diagnosis holds and you are still on an antidepressant that is partially working, the next move is often to add a second agent rather than swap the first one. The data for this is older than SPRAVATO and quietly stronger than most patients realize.

A 2022 network meta-analysis of 65 trials and more than 12,000 patients ranked the augmentation options that beat placebo for response: liothyronine (T3), nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine-fluoxetine, cariprazine, and lisdexamfetamine [4]. For remission, the cleanest signals were T3, aripiprazole, brexpiprazole, risperidone, quetiapine, and the olanzapine-fluoxetine combination.

The OPTIMUM trial — published in the New England Journal of Medicine in 2023, focused on adults 60 and older with TRD — found that adding aripiprazole to an existing antidepressant produced remission in 28.9% of patients, vs. 19.3% for those who instead switched to bupropion alone [5]. The takeaway is not that aripiprazole is the answer for everyone. It is that adding a second medication frequently outperforms switching the first one.

The two oral augmentations that get under-prescribed in private psychiatry, in our experience, are lithium and T3 (liothyronine). Both are old. Both are cheap. Both have evidence going back decades. Both require lab monitoring (lithium more than T3), and both are worth asking about by name.

The IV ketamine question

SPRAVATO is intranasal esketamine — the S-enantiomer of the racemic ketamine molecule. IV ketamine, the version used in infusion clinics, is the racemic form. They are related compounds, and they share the NMDA-receptor mechanism, but they are not the same drug, they are not dosed the same way, and patients who do not respond to one sometimes respond to the other.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) reviewed the evidence in 2020 and recommended IV racemic ketamine as a third-line treatment for adults with TRD, with Level 1 evidence supporting a single infusion [6]. A 2022 retrospective chart review of 424 patients in real-world infusion clinics found a 50% response rate and 20% remission rate within six weeks of starting infusions; after ten infusions, response rose to 72% and remission to 38% [7].

What this means in practice: if you completed a SPRAVATO course without the response you needed, you should still ask about IV ketamine. The dose curve is wider, the infusion duration is longer, and the response sometimes comes through where intranasal did not. It is not a guarantee. It is a real second look at the same mechanism.

ECT, said out loud

Electroconvulsive therapy carries a reputation it earned in the 1950s and never fully shook. The procedure now is not what it was then. Modern ECT uses brief-pulse, ultra-brief-pulse, or right-unilateral electrode placement under general anesthesia with a muscle relaxant; the seizure is short and the patient does not move. Memory effects are real but for most patients are limited to the period immediately around the treatment course and resolve over weeks to months [8].

The ELEKT-D trial, published in the New England Journal of Medicine in 2023, randomized 403 patients with non-psychotic TRD to either IV ketamine (twice weekly) or ECT (three times weekly) over three weeks. Response was 55.4% in the ketamine group and 41.2% in the ECT group, meeting the criteria for non-inferiority of ketamine [9]. ECT was associated with more cognitive side effects in the short term.

The clinical use is this: ECT is no longer a treatment of last resort. It is a remission-rate-leading option for severe or psychotic depression and a reasonable consideration for patients who have failed multiple medication trials and want a treatment with a long, well-documented record of effectiveness. If your prescriber treats it as the absolute final option, that framing is out of date.

Newer territory worth knowing about

Deep TMS (the H-coil)

Standard TMS uses a figure-8 coil that stimulates a focal region of left prefrontal cortex. Deep TMS uses an H-coil that reaches a broader and slightly deeper area. A 2024 multi-site phase IV study of 247 adults with depression treated with Deep TMS reported a response rate of 79.4% and a remission rate of 60.3% on the Hamilton scale after thirty sessions [10]. Patients who did not respond to standard TMS sometimes respond to Deep TMS, and vice versa, because the coils stimulate slightly different cortical territory.

Accelerated TMS protocols (the SAINT family)

Standard TMS is delivered once daily for six weeks. Accelerated protocols compress that course into ten sessions per day for five consecutive days, often with personalized targeting based on functional MRI. The original Stanford protocol and its descendants have produced rapid remission in TRD patients in published open-label work and are now offered at a small but growing number of clinical sites in the U.S. If your access to standard TMS is geographically constrained, an accelerated protocol can also collapse a six-week treatment burden into one week of daily appointments.

MAOIs, said out loud

The classic monoamine oxidase inhibitors — phenelzine, tranylcypromine, isocarboxazid — are the oldest antidepressants on the market and are now rarely prescribed because of dietary restrictions and drug-interaction risk. They also remain genuinely effective in patients with melancholic features and atypical features who have failed multiple newer agents. A 2022 international expert prescriber’s guide, endorsed by more than 70 specialists, argued that classic MAOIs “should always be considered in cases of treatment-resistant depression… and prior to electroconvulsive therapy” [11]. Most patients who could benefit from one have never been offered one.

Psilocybin, in clinical trials

Psilocybin-assisted therapy is not yet FDA-approved. The 2022 phase IIb trial published in the New England Journal of Medicine randomized 233 adults with TRD to a single 25 mg, 10 mg, or 1 mg dose of synthetic psilocybin with psychological support. The 25 mg group showed a significantly larger drop in MADRS scores at three weeks than the 1 mg control [12]. Phase III trials are ongoing. For patients who want this option today, the only legal path is a clinical trial, which can be searched on ClinicalTrials.gov by ZIP code.

Vagus nerve stimulation, for the most severely treatment-resistant

VNS is FDA-approved for chronic, severe TRD. The 2025 RECOVER trial analysis found that the primary outcome did not separate active from sham at twelve months, but a partial-response signal emerged on three of four depression scales when measured over a longer 10–12 month window [13]. The clinical implication is that VNS works slowly when it works, and is most appropriate for patients with multi-year, severe TRD who have exhausted the more rapid options.

Six things to ask your prescriber on the next visit

If you have read this far, you have the working vocabulary to have a different conversation than the one you have been having. The questions below are the ones a thoughtful prescriber will already be asking themselves; they are also the ones that move the conversation past “let’s try another SSRI.”

1. Is the diagnosis still right? Specifically, has bipolar II been screened with examples of hypomania, has untreated ADHD been considered, has trauma been adequately addressed, and have basic labs (TSH, B12, ferritin, fasting glucose) been recently reviewed?
2. What augmentation has not been tried? Lithium and T3 in particular — these are old, well-evidenced, and frequently passed over.
3. Am I a candidate for IV racemic ketamine? The mechanism overlaps with SPRAVATO but is not identical, and a non-response to one does not predict non-response to the other.
4. What does the modern ECT pathway look like at our local center? Specifically right-unilateral, brief-pulse protocols with cognitive monitoring.
5. Is Deep TMS or accelerated TMS available within driving distance? Different coils and different schedules sometimes succeed where standard TMS did not.
6. If I have failed three or more medications, would pharmacogenomic testing be useful? The benefit is small but real, and the result can prevent the next medication choice from being a guess.

What to remember on the drive home

The most important thing about treatment-resistant depression is the second word. It is not treatment-impossible. It is depression that has resisted two or three of the standard moves, which is a clinical situation with a long bench of additional moves and a long history of patients reaching remission after the first several options did not work. The map keeps going.

If you have completed both SPRAVATO and TMS without the response you were hoping for, you are not at the end of psychiatry. You are at a point where the next decision benefits from a careful, second-opinion-quality review of what has been tried, what has not, and which of the many remaining tiers — augmentation, IV ketamine, modern ECT, Deep TMS, accelerated protocols, MAOI reconsideration, VNS, or a clinical trial — fits the specific shape of your depression.

That review is what we do at Exxceed Wellness. It is not a sales pitch for one treatment. It is a conversation about which next step actually has the best chance of working for you, given what has and has not happened so far.