Most people are never handed this list. They get a dose increase, a new pill, and the words "give it a few more weeks." That's not wrong, but it's not the whole map. Here is what actually exists once the first line hasn't worked.
1. A more deliberate medication strategy
Before jumping tiers, a good prescriber often revisits the medication plan itself: switching to a different class, or adding a second agent that works alongside the first (this is called augmentation). Sometimes an earlier medication was stopped too early or never reached a full dose and was never truly given a fair trial. This is worth reviewing carefully rather than assuming pills as a whole have failed.
2. TMS (transcranial magnetic stimulation)
A non-invasive, drug-free treatment that uses focused magnetic pulses to stimulate the mood-regulating regions of the brain. It's FDA-cleared for depression that hasn't responded to medication, done in a clinic while you're awake, with no anesthesia and no medication side effects. Most people describe it as a tapping on the scalp and drive themselves home afterward. What TMS is actually like →
3. Esketamine (Spravato)
An FDA-approved nasal-spray medication specifically for treatment-resistant depression. It works on the glutamate system, a different mechanism than antidepressants, and is given in a certified clinic where you're monitored for about two hours afterward. It's usually used alongside an oral antidepressant, and for some people relief comes in days to weeks rather than months. What a Spravato appointment is like →
4. Ketamine therapy
The broader family of ketamine-based treatment, some given as an in-clinic infusion, some in other supervised formats. It's related to esketamine but used, dosed, and priced differently, and coverage varies more. It should always be doctor-supervised.
5. Structured, skills-based therapy
Approaches like cognitive behavioral therapy are not a consolation prize. For many people they work best layered with the options above, giving the brain new patterns while a medical treatment lifts the floor. Addressing foundations such as sleep, movement, and untreated medical conditions also makes every other treatment work better.
None of these are last resorts, and they're often combined into a single plan rather than tried one at a time. The question is rarely "is there anything left." It's "which of these fits me, and how do I get access to it."
One place that offers several of these under one roof
If you're in St. Charles County or the greater St. Louis area, Brain Recovery Centers is a doctor-supervised clinic that provides FDA-approved esketamine and FDA-cleared TMS for treatment-resistant depression, covered by most insurance including MO HealthNet. Their short screener will tell you honestly whether you're a candidate, or what to bring to your own doctor if you're not.
See if you qualify →