If you've been told you have treatment-resistant depression, the most important thing to know is this: treatment-resistant depression treatment options are broader than most people are ever told. "Resistant" describes how your depression has responded so far to the specific treatments you've tried. It doesn't predict that nothing will work. This post lays out the full roadmap clinicians use, from adjusting medication to augmentation, psychotherapy, and brain-based treatments, so you can have a more informed conversation with your provider.
First, confirm the diagnosis
Before changing strategy, make sure the depression is truly treatment-resistant and not pseudo-resistant. That can happen because of inadequate dosing, missed doses, an overlooked bipolar diagnosis, or an untreated medical condition. We covered that checklist in Is It Really Treatment-Resistant Depression? 7 Things to Rule Out First.
Why a roadmap matters: lessons from STAR*D
The NIMH-funded STARD study followed thousands of people with depression through as many as four sequential treatment steps. One clear lesson was that the chance of remission went down with each additional medication step (Rush et al., 2006). That's why, after two adequate trials, many experts recommend changing type* of strategy rather than just trying another similar pill.
Option 1: Optimize or switch medication
Optimize the current medication's dose if you've had a partial response and side effects allow.
Switch to an antidepressant from a different class, for example from an SSRI to an SNRI, bupropion, mirtazapine, or an older class such as a tricyclic or MAOI, under careful supervision.
Switching makes the most sense when the current medication hasn't helped at all or side effects are intolerable.
Option 2: Augmentation (adding a second medication)
When a medication is partly working, adding something often makes more sense than starting over. According to a 2024 review in American Family Physician, guideline-supported augmentation options include (Gaddey et al., 2024):
A second antidepressant with a different mechanism, such as bupropion or mirtazapine
An atypical antipsychotic. Several, including aripiprazole, brexpiprazole, cariprazine, and extended-release quetiapine, are FDA-approved as add-on treatments for major depression. Olanzapine-fluoxetine is FDA-approved specifically for TRD.
Lithium, a long-standing augmentation option with evidence for reducing suicide risk
Thyroid hormone (T3)
Each has its own side effect profile and monitoring needs. Metabolic effects with antipsychotics and blood levels with lithium are examples. A good provider will walk you through the trade-offs.
Option 3: Add or change psychotherapy
Psychotherapy isn't a "soft" option for TRD. Adding structured therapy, such as CBT, behavioral activation, or interpersonal therapy, to medication is a recommended strategy. If you've done therapy before, a different modality or a therapist experienced with chronic depression can make a difference. Read more about how therapy pairs with newer treatments in Spravato + Therapy.
Option 4: Spravato (esketamine) and ketamine
Esketamine targets the glutamate system rather than serotonin or norepinephrine. The FDA approved Spravato nasal spray in 2019 for adults with TRD, used with an oral antidepressant (FDA approval letter). In January 2025, the FDA also approved it as a monotherapy for adults with TRD (Johnson & Johnson). With an oral antidepressant, it's also approved for depressive symptoms in adults with major depression who have acute suicidal thoughts or behavior.
Here's what that looks like in practice. You give yourself the nasal spray in a certified healthcare setting under the Spravato REMS program while a provider supervises. We monitor you for at least two hours after every dose, including blood pressure, and you can't drive until the next day after a restful night's sleep. Per the label, treatment starts with twice-weekly sessions for four weeks, then weekly, then every one to two weeks, adjusted to your response. See What Happens During a Spravato Session?
Spravato isn't right for everyone. It isn't used in people with aneurysmal vascular disease, arteriovenous malformation, or a history of bleeding in the brain. Common side effects include dissociation, dizziness, nausea, and sedation, and no treatment comes with a guarantee.
IV ketamine is used off-label for TRD. We compared the two in Spravato vs. Ketamine Infusions.
Not sure whether it belongs on your roadmap? Book a free 15-minute consultation to see if Spravato is right for you.
Option 5: Brain stimulation treatments
NIMH describes several brain stimulation therapies used for depression that hasn't responded to other treatments (NIMH):
Repetitive transcranial magnetic stimulation (rTMS): a non-invasive outpatient treatment using magnetic pulses. See our comparison in Spravato vs. TMS.
Electroconvulsive therapy (ECT): performed under anesthesia, and still one of the most effective treatments for severe or treatment-resistant depression. Modern ECT is very different from its outdated portrayal in movies. Temporary memory side effects are the main concern to discuss.
Vagus nerve stimulation (VNS): an implanted device that's FDA-approved for chronic, treatment-resistant depression, generally considered after several other options
Option 6: Lifestyle foundations that support every option
None of these replace medical treatment for TRD, but they help every other treatment work better. A 2024 BMJ network meta-analysis found exercise, including walking, jogging, yoga, and strength training, was associated with meaningful reductions in depressive symptoms (Noetel et al., 2024). Sleep regularity, nutrition, reducing alcohol, and social connection matter too.
What about genetic testing?
Pharmacogenetic testing is widely marketed, but the AAFP review found the evidence for routine use in TRD is limited and doesn't recommend it as standard care.
How to choose your next step
Questions to discuss with your provider:
Has my current medication had a fair trial, and is it partly working?
Am I a better fit for augmentation, switching, or a non-oral option?
How quickly do I need relief? (Some options work faster than others.)
What can I realistically do in terms of time, travel, and cost?
What has worked, even partially, in the past?
Not sure if Spravato fits? Take our 5-minute self-assessment.
Frequently asked questions
What is the next step after two antidepressants fail?
Common next steps include switching to a different class, adding an augmenting medication, adding psychotherapy, or considering esketamine, TMS, or ECT. The right choice depends on your history, symptoms, and preferences.
What is the most effective treatment for treatment-resistant depression?
There isn't one best treatment for everyone. ECT has some of the strongest evidence for severe TRD, while augmentation, esketamine, and TMS are effective options for many people. A personalized plan matters more than any single ranking.
Is Spravato only for people who've tried many medications?
Spravato is FDA-approved for adults with TRD, which is generally defined as not responding adequately to at least two oral antidepressants. It's also approved, with an oral antidepressant, for depressive symptoms in adults with major depression with acute suicidal thoughts or behavior.
Does insurance cover treatment-resistant depression treatments?
Many plans cover options like augmentation, TMS, ECT, and Spravato, usually with prior authorization. See our Spravato insurance guide.
Map out your next step with us
At Stellar Genesis in Denver's Highland / LoHi neighborhood, we review your full treatment history and help you choose what comes next, whether that's Spravato or another path. Book a free 15-minute consult.
