Three powerful options for depression that hasn’t responded to medication — and how to understand the differences.
If you’ve reached the point of researching TMS, Spravato, or ketamine, you’ve usually already been through something.
Multiple medications. Maybe therapy. Months or years of trying, adjusting, hoping, and being disappointed. By the time someone starts comparing advanced treatments, they’re rarely curious in the abstract. They’re looking for something that finally works.
The good news is that these treatments exist, they’re well-studied, and they help people for whom standard approaches haven’t been enough. The confusing news is that they’re often discussed as if they’re interchangeable — three doors leading to the same place — when in fact they work differently, suit different situations, and come with different practical considerations.
Here’s a clear-headed way to think about all three, without the marketing gloss.
What they have in common
Before the differences, the shared foundation.
All three are options for depression that hasn’t responded adequately to traditional antidepressants — what clinicians call treatment-resistant depression. All three work through mechanisms that differ from standard SSRIs and SNRIs. And all three tend to act faster than traditional antidepressants, which can take six to eight weeks to show their full effect.
That’s the headline similarity, and it’s a meaningful one. For someone who has waited through multiple slow medication trials, the prospect of a treatment that works through a different pathway — and sometimes more quickly — is genuinely significant.
But that’s roughly where the similarities end.
TMS: stimulating the brain from outside
Transcranial magnetic stimulation is the most fundamentally different of the three, because it isn’t a drug at all.
TMS uses focused magnetic pulses, delivered through a coil placed gently against the scalp, to stimulate the brain regions involved in mood regulation. Nothing enters your bloodstream. There’s no medication circulating through your body, which means none of the systemic side effects people associate with antidepressants — no weight gain, no sexual side effects, no sedation, no emotional blunting.
You stay fully awake during treatment. There’s no anesthesia and no recovery time. Most people drive themselves to and from sessions and return to their day immediately afterward.
The trade-off is the schedule. A standard TMS course involves daily sessions over about six weeks. That’s a real time commitment, though accelerated protocols — which compress treatment into days rather than weeks — are changing that calculation for many patients.
TMS tends to be a strong fit for people who want a non-medication option, who’ve struggled with antidepressant side effects, or who prefer a treatment that doesn’t involve any altered state or sedation. It’s also among the most insurance-friendly of the three; standard TMS is widely covered for treatment-resistant depression when criteria are met.
Spravato: a regulated, in-office nasal spray
Spravato is the brand name for esketamine, a medication derived from ketamine and delivered as a nasal spray. It works through the brain’s glutamate system — a pathway entirely distinct from the serotonin-focused mechanism of traditional antidepressants.
The most important thing to understand about Spravato is that it’s tightly regulated, and that’s a feature, not a limitation. It’s FDA-approved specifically for treatment-resistant depression and for major depressive disorder with acute suicidal thoughts. It’s administered only in certified healthcare settings under medical supervision, with a monitoring period after each dose. You don’t take it home.
That structure exists because esketamine can cause temporary effects — sedation, dissociation, changes in blood pressure — that need observation. In exchange for that structure, patients get a treatment that’s standardized, studied, FDA-approved for their specific condition, and increasingly covered by insurance.
Spravato tends to suit people who want an advanced treatment with a clear regulatory track record and the possibility of insurance coverage, and who are comfortable with the twice-weekly-then-tapering in-office schedule that the early phase requires.
Ketamine: flexible, powerful, and off-label
Ketamine therapy is the most flexible of the three — and also the one that requires the most careful framing.
Ketamine is a long-established anesthetic that, at lower doses, has shown rapid antidepressant effects. It can be delivered several ways: intravenous infusion, intramuscular injection, intranasal and other routes. IV ketamine in particular has been studied extensively for severe and treatment-resistant depression, and for some patients it works when nothing else has.
The crucial distinction: ketamine is not FDA-approved for treating any psychiatric condition. Its use in depression is considered off-label. That doesn’t mean it’s improper — off-label prescribing is common and legitimate throughout medicine — but it does mean ketamine therapy is less standardized than Spravato, generally not covered by insurance for psychiatric use, and highly dependent on the quality and rigor of the clinic providing it.
Ketamine tends to be considered for patients with severe or treatment-resistant depression who are good candidates after careful screening, who understand the off-label nature of the treatment, and who are seeking a flexible, potentially rapid-acting option outside the more rigid Spravato framework.
So which one is right?
This is the question everyone arrives with, and the honest answer is that it depends on factors that can’t be sorted out from a blog post.
It depends on your diagnosis and how it was reached. On what you’ve already tried and how those trials actually went. On your medical history and any conditions that might rule one option in or out. On your insurance situation. On your schedule and how much disruption you can absorb. On whether you’d prefer a non-medication approach or are comfortable with one that involves a temporary altered state. And on the often-overlooked question of whether something other than treatment resistance — a missed diagnosis, an inadequate prior trial, an untreated medical contributor — is actually driving the problem.
That last point matters more than the choice between treatments. The best advanced treatment in the world won’t help if the underlying issue was a missed bipolar pattern or an untreated sleep disorder. Which is why the right starting point isn’t picking a treatment — it’s a thorough evaluation that figures out what’s actually going on, confirms that treatment resistance is real, and then matches the option to the person.
The bottom line
TMS, Spravato, and ketamine are three genuinely different tools, each suited to different people and situations. TMS is non-invasive, drug-free, and insurance-friendly, with a longer schedule. Spravato is the FDA-approved, regulated, in-office option with growing insurance coverage. Ketamine is the flexible, powerful, off-label option that depends heavily on the rigor of the clinic providing it.
But the most important decision isn’t which of the three to choose. It’s choosing to be evaluated carefully enough to know whether advanced treatment is the right path at all — and, if it is, which option fits the specific person you are.
For depression that hasn’t responded to standard care, there’s more available now than at any point in psychiatric history. The work is matching the right tool to the right problem. And that begins with being looked at closely.
Goldstone Psychiatry & Neuromodulation Center offers modern, personalized psychiatric care — including advanced treatments for depression that hasn’t responded to standard approaches. Telepsychiatry is also available throughout Texas.
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