Treatment-resistant depression (TRD) usually means major depression that has not improved enough after at least two antidepressants, each taken at an adequate dose for long enough and taken as prescribed. That is the most widely used definition, and a 2023 international review reports that the FDA and European Medicines Agency have adopted it.
Part of our guide: A Patient’s Guide to Ketamine and Spravato
It is a working definition, though. Experts have not settled on one standard, so two clinicians, two studies or two insurers can apply the term differently. The label also says less about you than it may seem to. It describes how past treatment went, and it does not mean nothing can help.
If you are thinking about suicide or are in danger, call or text 988 (988 Suicide & Crisis Lifeline), call 911 or go to the nearest ER.
Why there is no single definition
A review done for the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality found that no consensus definition existed. The most common version for major depression required at least two prior treatment failures, with confirmation of adequate dose and duration. For bipolar disorder, the most common version required one failure. The review also found no clear agreement on what counts as an adequate dose or duration, and only 17% of intervention studies enrolled people who met the most frequently specified criteria.
This has practical effects. When you read that a treatment worked for "treatment-resistant depression," the people in that study may or may not resemble you. It is fair to ask how the study defined the term. Spravato's main trials, for example, enrolled adults who had not responded adequately to at least two different antidepressants of adequate dose and duration in the current episode, which is one concrete version of the definition.
What "adequate" and "failed" usually involve
A clinician reviewing your history will usually want to know:
- Which medicines you took, including their class. Some definitions and insurers look for antidepressants that work in different ways.
- The dose you reached. A medicine stopped at a low starting dose may not count as a full trial.
- How long you took it. Short trials often do not count, though the required length varies by source.
- Whether you could take it consistently. Side effects, cost and access all affect this, and none of them are a personal failing.
- Whether it was the current episode. Many definitions and trials focus on the present episode of depression.
- What "not enough" looked like. Some improvement with symptoms remaining differs from no change at all, and your clinician needs to know which it was.
Insurers can be stricter than research definitions. For example, an Aetna coverage policy for Spravato looks for two antidepressants from at least two different classes, each used for at least 8 weeks within the past 5 years, and has further requirements. Criteria vary by plan and change over time, so a current check matters.
How common it is
The 2023 international review estimates that at least 30% of people with depression meet the common definition. It also notes that a lack of agreed definition makes precise estimates hard, so treat that as an approximate figure.
The large STAR*D study gives a sense of why this matters. Remission rates were 36.8% and 30.6% for the first and second treatment steps, then fell to 13.7% and 13.0% for the third and fourth. People who needed more steps also had higher relapse rates during follow-up. STAR*D is an older study with its own limits, and later steps had fewer people in them, but the pattern is a main reason clinicians take a second look after two unsuccessful trials.
Pseudo-resistance: when the label may not fit yet
The review uses the term "pseudo-resistance" for depression that looks treatment-resistant for other reasons. It says a significant share of people labeled with TRD fall into this group. The modifiable contributors it names include:
- an inaccurate diagnosis of major depression
- past or current treatment trials that were not adequate
- inaccurate assessment of whether treatment helped
- individual differences in how people metabolize antidepressants
- not being able to stay on treatment
Bipolar disorder deserves special mention. The review describes people with resistance to several antidepressants whose correct diagnosis should be bipolar disorder, and says the diagnosis should be reconsidered in anyone presenting with TRD. If you have ever had periods of unusually high energy, little need for sleep or risky behavior, say so even if they seemed like good times.
A good review also looks at other things that can keep depression going, such as anxiety, trauma history and major life stress, which the review links with poorer response or more severe illness. Physical health conditions are also more common in TRD. A clinician can decide which medical questions need checking in your case. This is one reason a full look at why depression is not responding comes before any change in treatment.
How to prepare your treatment history
You do not need perfect records. A simple list can make an appointment much more useful:
- Every antidepressant or mood medicine you can remember, with rough dates.
- The highest dose you recall, and pharmacy records if you can get them.
- How long you stayed on each, and why you stopped.
- What changed for better or worse, in your own words.
- Therapy you tried, including the type and for how long.
- Any hospital stays, brain stimulation or ketamine-related treatment.
- Family history of depression or bipolar disorder.
Please do not change or stop your medicine while you gather this. Stopping on your own can make things harder to sort out, and your prescriber should guide any change.
What options are studied for TRD
The review summarizes the evidence this way:
- Esketamine and intravenous ketamine are described as established treatments in TRD. Esketamine is FDA-approved for treatment-resistant depression in adults, alone or with an oral antidepressant. Ketamine for depression is off-label. See this overview of Spravato.
- Brain stimulation. Repetitive transcranial magnetic stimulation is described as effective, and the FDA has cleared it for TRD, and electroconvulsive therapy as an effective treatment for both acute and maintenance care. The National Institute of Mental Health has a general overview of these therapies.
- Adding certain medicines. Some second-generation antipsychotics have been shown to help as add-ons in people with a partial response.
- Extending, switching or combining antidepressants. The evidence for these is mixed.
- Psychotherapy. Manual-based therapies are not established on their own in TRD, but the review says they offer significant relief when added to antidepressants.
Each of these has its own risks, and the right order depends on your history, your health and how urgent things are. A psychiatrist can compare them with you in light of what you have already tried. No option works for everyone.
A note on suicidal thoughts
Long-lasting depression can wear people down. If thoughts of suicide appear or grow stronger, treat that as urgent, even if you have felt this way before and even if a new treatment has just started. Use the crisis options above, and tell your clinician.
Where to learn more
You can read about depression and treatment-resistant depression care at Mind Body Seven. To begin, request a consultation, and the intake team will confirm fit, scheduling and costs.
FAQs
Is "treatment-resistant depression" a formal diagnosis?
It is better understood as a description of how depression has responded to treatment. The underlying diagnosis is still major depression, and the term itself has no single agreed definition.
Does therapy that did not help count toward the definition?
It depends on the definition. The most common one centers on antidepressants, but some insurers and clinicians also ask about therapy. Your full history is still useful either way.
Does a TRD label mean depression will never improve?
No. It means the treatments tried so far have not done enough. Other options exist, though none works for everyone, and a clinician can walk through what is realistic for you.
Can teens have treatment-resistant depression?
Young people can have depression that does not respond to first treatments, and they need a specialist evaluation. Spravato is not approved for anyone under 18, so options differ from those for adults.
