Treatment-Resistant Depression Options: How to Choose Your Next Step

You gave the first antidepressant a fair shot, then a second one. You still don’t feel like yourself, and now a clinician has used the phrase treatment-resistant depression. That label can land like a verdict, but it’s really a signal to choose the next step differently.

Most antidepressants act on the same few chemical messengers in your brain, mainly serotonin and norepinephrine. When two of them haven’t worked, the options with the strongest evidence do something different: add a second mechanism, target a brain system called glutamate, or stimulate mood circuits directly. Matching that next step to your history takes precision.

The standard approach is stepwise: raise the dose, switch, or add a second medication. The 2023 Canadian depression guidelines still build on that sequence, recommending a switch when the first drug didn’t help or caused troublesome side effects, and an add-on when it helped partway. They also note that response rates for antidepressants alone appear to drop beyond the first switch. For many people, a well-chosen second step works, and that guidance rests on systematic reviews of the research.

But after two fair trials, repeating the same kind of step has diminishing returns, and at Siggy we’d rather match the next option to your history than reach for whatever comes next on a list.

Treatment-resistant depression options now include add-on medications, esketamine nasal spray, IV ketamine, transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and therapy alongside medication. Each has been tested in randomized trials, and each fits a different situation, depending on how much your current medication helped, how urgent things feel, and how much time you can give it. This guide puts them side by side so your decision rests on evidence.

What This Page Covers

• When Does Depression Count as Treatment-Resistant?
• Which Option Fits Which Situation?
• When Does an Add-On Medication Make Sense?
• What Should You Know About Esketamine (Spravato)?
• How Does IV Ketamine Compare With ECT?
• What Does TMS Involve, and How Well Does It Work?
• When Is ECT the Right Call?
• Does Therapy Still Help When Medications Haven’t?
• How Siggy Fits In
• The Bottom Line on Treatment-Resistant Depression Options
• Start Your Anonymous Intake

When Does Depression Count as Treatment-Resistant?

The most widely used definition, adopted by the FDA and the European Medicines Agency, is an inadequate response to at least two antidepressants. Each needs an adequate dose, an adequate length of time, and consistent use. A 2023 expert review estimates that at least 30% of people with depression meet that definition.

The same review found that a significant share of people labeled treatment-resistant are actually pseudo-resistant, meaning an earlier trial wasn’t adequate or doses were often missed. That’s why a good evaluation looks back before it looks ahead. The Canadian guidelines start by rechecking the diagnosis (including a missed bipolar disorder), looking for conditions that complicate treatment, and reviewing how consistently medication was taken.

Our guide to what causes treatment-resistant depression covers the common culprits, and our guide to auditing your past antidepressant trials helps you check whether your last two medications really counted.

Which Option Fits Which Situation?

The Canadian guidelines tie each option to a clinical situation, and the trials behind each row follow below.

Option	Often Considered When	How It’s Given	Main Trade-Offs
Add-on medication	Partial response, manageable side effects	Daily pill with your antidepressant	Sleepiness, restlessness, weight gain
Esketamine (Spravato)	Two or more failed antidepressant trials	Nasal spray in a certified clinic	2 hours of monitoring, no driving until next day
IV ketamine	Alternative to ECT, no psychosis	Infusion over 40 minutes	Dissociation, off-label use
TMS	Medication side effects are a concern	Weekday sessions for 4 to 6 weeks	Headache, time commitment
ECT	Psychotic, catatonic, or severely suicidal depression	Under anesthesia, about 3 times a week	Short-term memory effects, muscle aches
CBT added to medication	Ongoing symptoms on an antidepressant	Regular sessions with a therapist	Time, access to a trained therapist

When Does an Add-On Medication Make Sense?

If your antidepressant helped partway and the side effects are manageable, adding a second medication is usually the first move. The Canadian guidelines list aripiprazole (Abilify) and brexpiprazole (Rexulti) as first-line add-ons because of their efficacy and tolerability, with cariprazine (Vraylar) second-line because fewer studies support it.

In the VAST-D trial, 1,522 veterans whose depression hadn’t responded to at least one antidepressant course were randomized to different next steps. After 12 weeks, 28.9% of those who added aripiprazole reached remission, compared with 22.3% of those who switched to bupropion. Response rates were 74.3% and 62.4%. The gain was modest, aripiprazole caused more sleepiness, restlessness, and weight gain, and most participants were older men.

Switching still makes sense when the first medication did nothing or caused side effects you couldn’t live with. The Canadian guidelines call the evidence for switching inconsistent and note that older classes like tricyclics and MAOIs can help after poor response to newer antidepressants. Our guide to MAOIs explains their extra precautions.

What Should You Know About Esketamine (Spravato)?

According to Spravato’s prescribing information, esketamine blocks the NMDA receptor, a receptor for the brain chemical glutamate, though exactly how that produces an antidepressant effect is unknown. It’s FDA-approved for treatment-resistant depression in adults, on its own or with an oral antidepressant.

Speed is its main advantage. In the label’s main short-term trial, most of the difference from placebo was already present 24 hours after the first dose. In the ESCAPE-TRD trial, 676 people with treatment-resistant depression added either esketamine or extended-release quetiapine, an established add-on medication, to their SSRI or SNRI. At week 8, 27.1% of the esketamine group were in remission, compared with 17.6% of the quetiapine group. The trial was open-label with blinded raters and funded by Janssen, esketamine’s manufacturer.

The trade-off is logistics. Each dose is given in a certified clinic, where you’re monitored for at least 2 hours for sedation, dissociation (feeling detached or unreal), and blood pressure increases. In trials, 61% to 84% of people had dissociative or perceptual changes, which were temporary and happened on dosing days. You can’t drive until the next day after a restful sleep, and treatment starts at twice a week for the first 4 weeks.

Staying on it may protect your gains. In the SUSTAIN-1 trial, people in stable remission who continued esketamine had a 51% lower risk of relapse than those switched to a placebo spray, with both groups staying on their oral antidepressant. Janssen researchers also led that trial. The Canadian guidelines rate esketamine and ketamine as second-line options, mainly because of side effects and the monitoring they require.

Spravato is also approved, with an oral antidepressant, for adults with depression and acute suicidal thoughts or behavior, though the label notes it hasn’t been shown to prevent suicide. If you’re having thoughts of suicide, call or text 988 or call 911. Our guide to ketamine and esketamine for depression covers what a session is like.

How Does IV Ketamine Compare With ECT?

IV ketamine, esketamine’s older relative, is given as an infusion and isn’t FDA-approved for depression. A consensus statement from 2017 treats its psychiatric use as off-label and lays out safety considerations for it.

The ELEKT-D trial randomly assigned 403 people with treatment-resistant depression without psychosis, all referred for ECT, to IV ketamine twice a week or ECT three times a week for 3 weeks. Response rates were 55.4% with ketamine and 41.2% with ECT, which showed ketamine was noninferior. ECT was linked to a drop in memory recall that gradually recovered, while ketamine was linked to dissociation.

The trial was open-label, excluded psychotic depression, and more people assigned to ECT withdrew before their first treatment, so it doesn’t settle which treatment is better for everyone.

What Does TMS Involve, and How Well Does It Work?

Transcranial magnetic stimulation uses a magnetic coil on your scalp to stimulate the left dorsolateral prefrontal cortex, an area involved in regulating mood. You’re awake throughout, and the Canadian guidelines note that people may be able to keep working or studying during a course.

In the THREE-D trial, 414 people with treatment-resistant depression had sessions 5 days a week for 4 to 6 weeks, using either standard 37.5-minute sessions or a newer form called intermittent theta burst stimulation, which takes about 3 minutes. Both groups improved by a similar amount, and headache was the most common side effect, reported by about 65% in each group.

In 2022, the FDA cleared an accelerated, MRI-guided protocol called SAINT that condenses treatment into 5 days of 10 sessions each. Like standard TMS, it’s cleared for adults whose depression hasn’t improved enough on antidepressant medication in the current episode. FDA’s clearance summary notes that its clinical data came from 70 patients at a single site, and that effectiveness hasn’t been established beyond 4 weeks after treatment.

Outside of emergencies, the Canadian guidelines suggest considering TMS before ECT because it’s less invasive. Our guide to TMS for treatment-resistant depression walks through a course week by week.

When Is ECT the Right Call?

ECT has decades of evidence behind it. In a Lancet meta-analysis, real ECT outperformed simulated ECT, and ECT outperformed medication across 18 trials with 1,144 participants. That analysis is more than two decades old and covered depression broadly, but current guidelines still recommend ECT for the most severe cases.

The Canadian guidelines list ECT as a first-line choice in severe situations: depression with psychotic or catatonic features, severe suicidal thoughts, a deteriorating physical condition, or a past good response to ECT. Our guide to ECT explains what modern treatment involves.

Does Therapy Still Help When Medications Haven’t?

It often does. The CoBalT trial enrolled 469 primary care patients in the UK who were still depressed after at least 6 weeks on an antidepressant. Adding cognitive behavioral therapy (CBT) to their usual care roughly doubled the response rate at 6 months, 46% compared with 22%.

That fits the 2023 expert review, which concluded that structured psychotherapies aren’t established as a standalone treatment for treatment-resistant depression but offer significant relief when added to antidepressants. Our guide to CBT explains what sessions look like.

How Siggy Fits In

Treatment-resistant depression often comes down to what happened during each medication trial, and that’s hard to reconstruct when appointments are short and far apart. You shouldn’t have to retell your story every time you see someone new.

Siggy starts with a free, anonymous intake, no name or email required. A licensed prescriber reviews your intake, including the medications you’ve already tried, before anything is prescribed. You get a summary you can keep and share with any clinician, including a TMS, esketamine, or ECT specialist.

Siggy’s prescribers focus on anxiety, depression, and SSRI-based treatment. Siggy is a good place to check whether earlier trials got a fair test and to stay supported between visits, so side effects or doubts don’t quietly end a trial early. Esketamine, IV ketamine, TMS, and ECT happen in specialty clinics, and your prescriber can help you understand when a referral makes sense.

This article is for education and isn’t a substitute for care from a licensed clinician.

The Bottom Line on Treatment-Resistant Depression Options

Treatment-resistant depression means the usual first steps haven’t worked, not that nothing will. A partial response points toward an add-on medication, while severe or urgent depression points toward ECT. Esketamine offers speed at the cost of clinic visits and monitoring, IV ketamine is a credible alternative to ECT, TMS is less invasive but more time-intensive, and adding therapy is worth discussing at any stage. If you’re unsure whether your current medication has had a fair chance, our antidepressant decision path walks through the 8-week mark.

Start Your Anonymous Intake

If you’re in crisis or thinking about harming yourself, call 911 or call or text 988 first. If you’ve tried antidepressants without the relief you hoped for and want a prescriber to look at your whole history, start your anonymous intake. It’s free, there’s no name or email required, and a licensed prescriber reviews everything before anything is prescribed. Your summary is yours to share with whoever helps you next.