Treatment-Resistant Depression: What It Is and What to Do Next

Treatment-resistant depression (TRD) is most commonly defined as the failure of two or more adequate antidepressant trials, each of sufficient dose and duration, during the current depressive episode.

About 3 in 10 US adults treated with medication for depression in a year meet this definition. When that happens, the first step is a careful re-evaluation, because some cases have causes that can be addressed. When no identifiable cause is found, several options are available, including add-on medicines, therapy and TMS. Many people improve over time.

What is treatment-resistant depression?

Treatment-resistant depression is a form of depression that has not improved sufficiently despite trying at least two different antidepressants during the same episode. Each one should have been given at an adequate dose and for an adequate length of time. Experts often disagree on the exact definition, and they may also differ on what counts as an adequate dose and an adequate length of time. It's a judgment a clinician makes based on the individual's treatment history.

Treatment-resistant depression (TRD) is also known by other names, such as refractory depression, treatment-refractory depression or medication-resistant depression. Some experts use an even broader term, difficult-to-treat (sometimes called hard-to-treat) depression, for depression that keeps causing significant burden despite usual treatment.

How common is treatment-resistant depression?

About 3 in 10 US adults treated with medication for depression in a year meet the definition of treatment-resistant depression. The more treatments that have failed within an episode, the higher the medical costs and the lower the quality of life, which is a reason to look at the next step early.

Not responding fully to the first antidepressant is common. In STAR*D, a large real-world study of depression treatment, about half of the people taking their first antidepressant improved substantially. About one in three reached remission, meaning few or no symptoms were left. Many of those who improved did so only at or after 8 weeks.

As people moved through up to four medication steps, the chance of remission became smaller with each step: about 31% at the second step, and 14% and 13% at the third and fourth.

What causes treatment-resistant depression?

Although sometimes no specific factor can explain treatment resistance, in many cases one or several factors in combination contribute to it. Here are some of the common factors, several of which can be addressed:

Inadequate medication trial: An earlier medicine may not have reached an adequate dose or been taken long enough. It may also have been taken irregularly or stopped, often because of side effects. This is sometimes called pseudo-resistance, and it is a common reason a treatment seems to fail. Side effects can also look like symptoms of depression, which is why the treatment history is reviewed in detail.

Co-occurring psychiatric and medical conditions: Other conditions alongside depression can hold back its response to treatment. Anxiety disorders have the strongest link. Others include personality disorders, substance use, ADHD, PTSD, medical problems such as sleep apnea, thyroid disease or anemia, and ongoing stress.

Misdiagnosis: Re-evaluation sometimes shows that what looked like depression is part of bipolar disorder, which is treated differently.

Type of depression: Some features of the depression itself are linked to a weaker response to first antidepressants. These include more severe or recurrent episodes, an earlier age of onset, and prominent loss of interest and pleasure. These are associations, and none of them decides an individual outcome.

A note on genetic testing: Genes can affect how the body processes a medicine, and genetic tests are marketed to guide the choice of antidepressant. The evidence for them is limited. They can help predict side effects, but in a large trial they improved remission only slightly and briefly.

How does a mental health professional re-check depression that hasn't responded?

When depression has not improved, the standard first step is a careful re-evaluation before a new treatment is chosen. The re-check usually follows this order.

1. How much has changed. Besides low mood or loss of interest, depression includes changes in sleep, energy, appetite and concentration, feelings of guilt, and thoughts of death or suicide. The clinician goes through each of these symptoms to see which have improved, which have not, and how severe the remaining ones are. This shows whether there has been a partial response (feeling somewhat better but still having clear symptoms) or no response. A partial improvement with few side effects often points toward adding to the treatment. No improvement, or troublesome side effects, more often points toward a change.
2. Whether each treatment had a fair trial. For every medication tried, the clinician checks the dose, how long it was taken, and whether it was taken regularly.
3. Whether other conditions are present. The clinician asks about co-occurring conditions such as anxiety, sleep problems, past trauma, alcohol or substance use, and ADHD.
4. Whether the diagnosis is correct. The clinician asks about family history and about past highs and lows, including mania or hypomania. These are periods of unusually high or irritable mood, with more energy and less need for sleep.
5. Medical and life factors. The clinician reviews medical conditions that can affect mood, such as thyroid problems, anemia and sleep apnea, along with any medication that could affect mood and any ongoing stress.

Other conditions are treated alongside the depression, and a diagnosis of bipolar disorder changes the treatment approach. Sometimes no other explanation is found: the medication was taken at an adequate dose, consistently, and nothing else accounts for the lack of improvement. In that case, the options in the next section are considered.

What are the treatment options for treatment-resistant depression?

When depression has not responded, the options fall into a few groups: switching to a different antidepressant, adding a second medicine, adding psychotherapy, brain stimulation, and esketamine or ketamine. Guidelines recommend choosing the order together, based on what has already been tried, the strength of the evidence, side effects and personal preference. No treatment works for everyone. The next section compares the chances of improving with each option.

Switching to a different antidepressant

Switching is a common next step, but the evidence for it is inconsistent. In studies, switching has not done better than staying on the same medicine, and the chance of remission becomes smaller after the first switch.

Adding a second medicine

Adding a medicine keeps whatever benefit the first one has already given. Atypical antipsychotics, a newer group of antipsychotic medicines used at low doses for this purpose, have the most consistent evidence as add-ons. Several are FDA-approved for use alongside an antidepressant in major depression, and one combination is approved specifically for TRD. Their side effects can include restlessness, weight gain, changes in blood sugar or cholesterol, and sleepiness.

Lithium and thyroid hormone are older add-ons. They are used off-label for depression, which is common in medicine when the evidence supports it, and both require blood tests to monitor levels. Adding a second antidepressant is another option, with less evidence but generally fewer side effects.

Adding psychotherapy

Cognitive behavioral therapy (CBT) is a structured form of talk therapy. Adding it to medication has good evidence. In a large UK trial of people who were still depressed despite taking an antidepressant, adding CBT helped more people improve, and the benefit lasted about four years. Guidelines recommend it as an add-on treatment.

Transcranial magnetic stimulation (TMS)

TMS uses magnetic pulses to stimulate the brain, and it has been FDA-cleared for depression since 2008. It's generally recommended when first-line treatments, such as antidepressants, have not adequately relieved the depression. In clinical trials of people who had not improved after two antidepressants, adding TMS led to nearly three times the rate of remission seen with sham (placebo) treatment.

It is non-invasive and generally well tolerated; side effects are usually mild, such as temporary scalp discomfort. It doesn't affect memory or thinking, doesn't require anesthesia, and people can keep working or attending school during the treatment course. Learn more about how TMS is used for depression.

Esketamine and ketamine

Esketamine is a nasal spray that is FDA-approved for TRD, either alone or with an oral antidepressant. It can cause sleepiness, a feeling of detachment (dissociation) and slowed breathing. For that reason, it is given only in certified clinics, with at least two hours of monitoring after each dose.

Ketamine given by IV infusion is approved by the FDA only as an anesthetic, so its use for depression is off-label. Studies show it can work quickly, and it also requires monitoring of blood pressure and dissociation. We don't offer esketamine or ketamine at Everhealth.

How is the next treatment chosen?

The next treatment is chosen together by you and your clinician, weighing a few standard factors.

The first is what has already been tried and how it went. Past medicines, the doses reached and any side effects all shape what comes next, along with whether the last treatment helped partly or not at all.

The second is the strength of the evidence for each option and its likely side effects.

The third is the chance of improving with each choice. After two medicines have not worked, the research gives a rough guide:

• Another medication step: about 14% reached remission at a third step and 13% at a fourth.
• Adding TMS: in the largest trial comparing two standard TMS methods, 47–49% responded (symptoms dropped by at least half) and 27–32% reached remission.
• Adding esketamine or an add-on antipsychotic: in one trial, 27% and 18% reached remission at 8 weeks.
• Adding CBT (after at least one antidepressant): 46% responded at 6 months, compared with 22% with usual care alone, and more people also reached remission.

The figures come from different studies with different patients, and some report response while others report remission, so they are a guide to the odds rather than an exact ranking.

The fourth is your preferences and practical life. A standard TMS course means weekday visits over several weeks, while an accelerated schedule takes days or a few weeks. Some accelerated schedules are FDA-cleared, and others are used off-label; we offer both. Esketamine requires monitoring in a clinic after each dose. Add-on medicines bring their own side effects and, for some, regular blood tests. Cost, insurance coverage and a wish to avoid more medication also matter.

Finally, severity and safety can change the order. In my practice, when depression is severe, for example with psychotic features or serious suicidal thinking, inpatient hospital care is usually considered first, and further treatment is planned from there. That plan may or may not include electroconvulsive therapy (ECT), a treatment given under general anesthesia. If a step does not work, the plan is reviewed again.

Can treatment-resistant depression get better?

Yes, it often can, although it may take more than one step, and it can return after improving.

Among people whose depression had been treatment-resistant for a long time, about 4 in 10 recovered within 10 years. At the same time, relapse after remission was common in people who had needed several treatments, which is why follow-up continues after you feel better.

Treatment-resistant depression is also linked to a higher risk of death from suicide and accidents. That risk is one reason to stay in active treatment and in close contact with your care team. If you are having thoughts of suicide, call or text 988 to reach the Suicide & Crisis Lifeline, or go to the nearest emergency room.

What should you do next?

If two or more treatments have not helped enough, ask for a full re-evaluation by a mental health professional, such as a psychiatric evaluation.

Before the visit, write down each medicine you have taken, the highest dose, how long you took it, any side effects, and why it was stopped. Add any therapy you have tried, and bring the list to the evaluation.

Do not stop or change your medicine on your own. If you notice side effects or your symptoms get worse, contact your prescriber right away.

Ask about all of your options, including TMS. Standard and accelerated TMS, including FDA-cleared and off-label schedules, are offered at our Tomball office. Accelerated schedules suit anyone who cannot commit to six weeks of daily visits, including people who live farther away. See whether TMS is right for you.

Everhealth is not a crisis service. If you are in crisis, call 911, go to the nearest emergency room, or call or text 988.

This content is educational and not a substitute for a professional evaluation.

Frequently asked questions

Does talk therapy work on its own for treatment-resistant depression? Structured talk therapies, such as CBT, have not been shown to work on their own in treatment-resistant depression. When they are added to an antidepressant, they help more people improve, which is why guidelines recommend them as an add-on to medication.

Can I have TMS while taking antidepressants? Usually, yes. In most TMS trials, people continued their medication during treatment without changing the dose, and in the largest head-to-head TMS trial participants stayed on stable medicines throughout. Some reports suggest that certain medicines, such as benzodiazepines, may lower the response to TMS. Your clinician reviews everything you take before a course begins.

How long should an antidepressant be tried before deciding it isn't working? Guidelines look for early improvement, meaning symptoms drop by at least 20% within the first 4 weeks. Without early improvement by then, the chance of a response at 8 to 12 weeks is low, and the dose is usually increased or the medicine changed. Any change should be made with your prescriber.