Written by: Elle Warren
Reviewed by: Nina Kalus, PsyD., and Yalda Safai, MD, MPH
Before escalating treatment, confirm true treatment-resistant depression (TRD) rather than pseudo-resistance, most often from inadequate dose or duration, non-adherence, or an unrecognized comorbidity.
After two failed antidepressant trials, the likelihood of remission with additional medication trials declines;consider options beyond medication alone.
Established TRDoptions include medication switching or augmentation, psychotherapy, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT). Newer-generation options include esketamine, IV ketamine, and accelerated TMS protocols.
TMS is one established, noninvasive option among several next-line treatments. The appropriate choice depends on treatment history, symptom severity, urgency, tolerability, access, and patient preferences.
When a patient has failed the standard first- and second-line approaches to major depressive disorder (MDD), the next step isn’t always obvious. The best option depends on symptom severity, treatment history, and logistical and financial barriers. However, despite the name, there is treatment for treatment-resistant depression, which occurs in about 31% of people treated for depression. Once you confirm true resistance, it’s time to consider the full range of evidence-based, next-step options beyond medication alone.
There is some debate among clinicians about the precise definition of treatment-resistant depression (TRD), also referred to as refractory depression, but the general consensus is two or more failed trials of antidepressants.
However, it’s important to rule out what’s known as pseudo-resistance. In this case, a patient may appear treatment-resistant because:
Often, says Stefani LaFrenierre, MD, psychiatrist and founder of Resiliency Mind+Body Medicine, “Patients aren’t fully treatment-resistant, they’re treatment-mismatched.”
Confirming true resistance matters because if a patient hasn’t received an adequate medication trial, the next best step may be optimization rather than escalation. If two medication trials have truly failed, continuing with a drug-first approach becomes less likely to provide results.
The STAR*D trial—a large, foundational study on sequential treatment for major depressive disorder—established that patients are far less likely to reach remission after two failed medication trials.
The four treatment steps and remission rates were:
The cumulative picture is more encouraging: across all four sequential treatment steps, an estimated 67% of patients eventually reached remission. That figure is a projection: it assumes the roughly one-third of participants who dropped out would have fared like those who stayed.
But the steep drop after two failed steps suggests that it makes sense to evaluate options beyond additional treatment-resistant depression medication, including TMS, which STAR*D did not assess.
The established treatment-resistant depression treatment options include medication strategies (i.e. switching drug classes or augmentation), psychotherapy, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT).
Established TRD options at a glance
| Response/ remission rate |
Time to response | Invasiveness | Discontinuation rate | Typical next step in sequencing | |
|---|---|---|---|---|---|
| Medication strategies | Varies, remission is typically <14% | 4-8 weeks | Noninvasive | Varies, ~25% | Another medication trial, psychotherapy, TMS, or ECT (depends on patient) |
| Psychotherapy | Varies by type, response as high as 75%, remission up to 40% | 8-12 weeks | Noninvasive | Varies, but typically lower than medication | TMS or ECT |
| Transcranial magnetic stimulation (TMS) | Standard TMS: 30% response, 19% remissionDeep TMS: 81.6% response (~4 out of 5 patients), 65.3% remission (~2 out of 3 patients) |
4-6 weeks | Noninvasive | ~4.5% | Emerging strategies such as esketamine or IV ketamine, ECT |
| Electroconvulsive therapy (ECT) | 74% response, 52% remission |
As soon as one session | More invasive | ~34% | TMS, emerging strategies such as esketamine or IV ketamine |
Note: Response and remission data is difficult to compare directly, due to variables in patient population and other study factors. This data provides a general overview.
There are two primary medication strategies that are used in TRD treatment: switching medication classes or augmenting with an additional medication. The classes of drugs used to treat depression, and their average range of efficacy, include:
Medication tolerability varies between individuals. That said, MAOIs and TCAs tend to have more serious side effects, which is why SSRIs and SNRIs are more common first-line approaches.
With augmentation, a new medication is added alongside the antidepressant. According to a 2022 systematic review and meta-analysis, the most effective augmentation strategies for treatment-resistant depression include lithium (15.9% remission rate), T3 thyroid hormone (24.7% remission rate), and atypical antipsychotics (exact remission rate unknown, but in a 2015 meta-analysis, they showed significantly greater efficacy compared to placebo).
Sam Zand, MD, psychiatrist and CEO of Anywhere Clinic, explains how to determine whether to switch classes or augment. “If it [the antidepressant] worked a little bit, we would try an augmentation. If it didn’t work at all, then we would switch to a different class.” He also notes that if a patient is having side effects, even ones that seem minor, then the medication is likely not going to be sustainable for them long-term and is worth switching.
Psychotherapy shouldn’t be treated as an afterthought when it comes to treatment-resistant depression treatment options. Multiple research studies have found it to be especially effective when used in conjunction with other treatment strategies, such as medication and TMS. The most common and effective types of psychotherapy used to treat depression and TRD include:
While efficacy varies by type of psychotherapy and patient population, in a large trial of patients with treatment-resistant depression, 43% who received CBT maintained a response rate at nearly four years. CBASP, which was specifically developed for chronic depression, has demonstrated an 84% response rate and 44% remission rate among intensive inpatient program patients.
MBCT, which combines meditation with cognitive therapy, actually shows an improved response rate over time. One study of over 100 patients with TRD showed a 30% response rate at 8 weeks and 44% at 52 weeks.
This data, plus the post-CBT relapse data above, points to a notable advantage of psychotherapy compared to medication: its durability. Patients are able to gain insight and skills that they can carry with them indefinitely.
TMS is FDA-approved to treat MDD and works by delivering magnetic pulses to the brain to alter brain activity. There are two primary types of TMS: standard TMS (also known as rTMS) and BrainsWay’s patented Deep TMS.
Standard TMS, which is the original, first-generation type of TMS, is delivered with a figure-8 coil. It has a more narrow and surface-level reach compared to Deep TMS, with a 30% and 19% rate of response and remission, respectively, among patients with TRD. Deep TMS targets a wider, deeper area of the brain, leading to significantly stronger outcomes. Deep TMS has a respective 80% and 36% rate of response and remission.
TMS can also alleviate co-occurring anxiety symptoms and be a highly effective complement to other treatments, particularly medication and psychotherapy. In a 2023 meta-analysis, patients who received TMS while taking an antidepressant were 2.8 times as likely to experience remission compared to those who took an antidepressant and received a sham TMS treatment. TMS combined with psychotherapy has shown a 66% response rate and 56% remission rate, with 60% sustained remission at follow-up.
ECT works by introducing a brief controlled seizure. While the goal is to establish a new rhythm within the brain’s neural functioning, its mechanism is not fully understood. Due to its intensity, patients are given general anesthesia during treatment. ECT has a poor reputation in the media and pop culture, often referred to as “shock treatment” and depicted as a painful, traumatic process. The reality is that ECT can be a highly effective treatment for TRD, with an average response and remission rate of 74% and 52%, respectively.
Side effects—most notably short-term memory effects—are the tradeoff with ECT. Because of this potential to lead to ongoing cognitive impact, Dr. Zand explains that ECT is typically thought of as a last-line treatment for TRD.
The psychiatric field is constantly evolving, and there are a variety of newer treatment options with strong bodies of evidence, including esketamine, IV ketamine, theta-burst and accelerated TMS, and psilocybin.
Esketamine is a potent version of ketamine administered by a clinician via nasal spray and is FDA-approved for TRD. According to a systematic review published in Current Neuropharmacology, ketamine is rapidly (within 24 hours) effective at reducing symptoms of depression—and has even been found to reduce suicidality. The side effect profile is generally low and decreases as treatment goes on. The most common adverse reactions include nausea, dissociation, dizziness, and headache. That said, it can slow reaction times, so driving afterward is prohibited.
Both Dr. Zand and Dr. LaFrenierre underscore the effectiveness of esketamine. However, Dr. LaFrenierre says, it’s not always a long-term solution. “Over time, the efficacy of it starts to become similar to being on a maintenance antidepressant. About 30% of our patients stay in remission at the one-year mark with esketamine.”
For ongoing treatment she says, “We transition into TMS to continue that momentum.”
This is another way to receive ketamine treatment and shows similar levels of efficacy to esketamine, although it may act faster. Patients can notice results as soon as 40 minutes post-infusion. As with esketamine, driving afterward is not allowed. Both types of ketamine treatment require several sessions spread out over several weeks, but of course, an IV is more invasive than nasal spray.
Many TMS devices now have newer, FDA-approved protocols that make treatment sessions shorter and, in the case of accelerated TMS, allow for a faster course of treatment.
The theta-burst protocol, available with both standard TMS and Deep TMS devices, shortens the length of treatment sessions. The accelerated TMS protocol, also approved between both types of TMS, compresses the length of treatment sessions as well as the course of treatment. Sessions are completed in just 4-10 days, depending on the device. BrainsWay’s proprietary SWIFT protocol, for example, is 38 sessions. The accelerated protocol used for most other devices, the SAINT protocol, is 50 sessions.
Theta-burst and accelerated TMS display similar efficacy to the typical length and course of treatment, but the shorter sessions and course of treatment allows for faster results and easier scheduling.
CTA: BrainsWay offers devices for Deep TMS and Accelerated TMS
Psilocybin, the psychedelic compound found in certain mushrooms, is gaining momentum in psychiatry. In April 2026, an executive order directed federal agencies to speed up research and access to psychedelic treatments for serious mental illness. In July, Compass Pathways released six-month results from its trial of synthetic psilocybin for treatment-resistant depression: 39% of patients on the high dose saw a meaningful drop in symptoms after two doses, and on average that benefit lasted six months. The results are promising but modest, and they come from the company developing the drug. They haven’t been peer-reviewed yet.
The need for faster, more effective treatment options for TRD has driven research into several mechanisms, including:
Evidence for these approaches varies quite a bit. Glutamine receptor modulators have produced approved treatments; the others remain earlier in development and are worth watching as research progresses.
Choosing the best TRD treatment option for a specific patient comes down to a number of factors, including the severity of their symptoms, prior treatment response, and logistical and financial barriers.
“Although we want to prioritize what’s best, we have to also incorporate [the patient’s] social situation,” says Dr. Zand, “and that includes cost, insurance coverage, transportation, schedule, and urgency.”
TMS is one established option with the broader TRD next-line treatment options framework, displaying significant rates of response, remission, and durability with minimal side effects. Dr. LaFrenierre says Deep TMS is the go-to next-line treatment option at her clinic. “We have a 70%-75% remission rate, and an 85%-90% response rate.”
TMS is also covered by insurance, though some plans may require a certain number of medication failures before approving.
CTA: BrainsWay offers FDA-cleared Deep TMS systems
After two failed antidepressant trials, the chances of TRD patients finding relief from medication alone dramatically declines. However, treatment-resistant major depression is treatable when considering the broader landscape of options, such as psychotherapy, TMS, ECT, and newer-generation treatments like esketamine, IV ketamine, and newer TMS protocols. When choosing the best next step for a specific patient, providers should factor in symptom severity, treatment history, and logistical barriers.
There is no single gold standard treatment for every patient with treatment-resistant depression (TRD), as it depends on their symptom severity, treatment history, and any logistical barriers. ECT, Deep TMS, and psychotherapy have some of the strongest efficacy data. When a case calls for a rapid response, the best options tend to include esketamine, IV ketamine, accelerated TMS, and ECT.
In practice, treatment resistance generally means that a patient has failed to respond adequately to at least two appropriate antidepressant trials. Before escalating treatment, providers should rule out pseudo-resistance caused by inadequate dosing or duration, inconsistent adherence, diagnostic uncertainty, untreated comorbidities, substance use, interactions, or other medical factors.
Newer-generation options for treatment-resistant depression (TRD) include esketamine, IV ketamine, theta-burst and accelerated TMS protocols. Investigational approaches—such as psilocybin, currently available only through clinical trials, and approaches targeting inflammatory pathways—remain in development. Their regulatory status and evidence bases differ quite a bit: esketamine is FDA-approved for TRD and TMS is FDA-cleared, while IV ketamine is used off-label..
After a patient has failed two or more adequate antidepressant trials, TMS, or transcranial magnetic stimulation, becomes a reasonable candidate for the next-line treatment discussion. Providers should consider referral particularly when the patient wants a noninvasive option, has concerns about medication tolerability, or hasn’t achieved adequate benefit from medication-based strategies.
Reference:
Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–1917.
