I’ve tried two antidepressants and still feel unwell. Is it treatment-resistant depression?

When does an antidepressant count as an adequate trial?

When reviewing a medical history, I would start with four questions about each treatment instead of asking how many pills you have tried: What did you actually take? How long were you at a therapeutic dose? What changed in your life while you were taking it? Why did you continue or stop it? The answers help distinguish situations that call for different decisions. ^[3]

These are clinical distinctions. They do not reflect how hard someone has tried. If nausea, sedation, or sexual side effects make a regimen difficult to maintain, it needs review. ^[3]

How long is long enough?

No single number applies to every medication and every person. Some consensus statements use four to eight weeks at an adequate dose as a guide. NICE offers a practical recommendation: review the case if there has been no improvement after four weeks at a therapeutic dose. That guidance calls for a review. It does not require an automatic medication switch that day or mean you should wait four weeks to report that you are doing worse. ^[2]

When you start counting also matters. If the first few weeks were spent raising the dose gradually, the date of the first prescription does not tell you how long the person was at the therapeutic dose. If months have passed without a benefit that the person or clinician can identify, giving it more time calls for a reason and a date to review the decision. ^[4]

Related reading: My antidepressant isn’t working. How long should I wait?.

Severe, chronic, and treatment-resistant depression describe different things

Severe describes symptom intensity, impairment, and risk. Chronic or persistent describes duration. Treatment-resistant describes what happened after adequate treatments. Someone can have severe depression in a first episode without ever having taken an antidepressant. Someone else may have been ill for a long time without access to two adequate trials. Both should get the care they need regardless of whether they meet a criterion for resistance. ^[3]

There is also a difference between responding and recovering. Taking a shower each morning, cooking, or going to work again can be substantial progress. If it is still hard to concentrate, enjoy a conversation, or look forward to anything, there are meaningful goals left to work toward. A scale such as the PHQ-9 can help track change. It is still important to ask, “What part of your life have you yet to get back?”. ^[3]

What should be reviewed before confirming treatment-resistant depression?

First, look at the history of your mood, including times when you seemed to be doing unusually well. I would ask about more than the weeks of sadness. I would also ask about periods that stood out from your usual self, with much less need for sleep without fatigue, unusual energy, feeling sped up, or risky decisions. Some people remember hypomania as a particularly productive time and do not bring it up when seeking help for depression. If the history suggests bipolar disorder, the treatment strategy changes. A lack of response to two antidepressants is not enough to establish bipolar disorder. ^[5]

Next, identify the symptom that remains and what else might explain it. Continuing to feel sad and hopeless differs from having your mood improve but feeling drowsy all day since the last dose change. I would ask about sleep, pain, anxiety, alcohol, and other medications. Depending on the findings, it may make sense to investigate a physical condition, such as a thyroid disorder, or coordinate care with another professional. An integrative approach asks which finding would change the decision. ^[5]

Finally, consider what treatment you could actually access. A note saying “psychotherapy recommended” does not mean you received it. If scheduling, cost, or caregiving responsibilities made it necessary to stop, that does not establish that therapy failed. The same applies to medication you could not continue. This is sometimes called apparent resistance. The term describes uncertainty about whether the treatment had an adequate trial, while the patient’s suffering is real. ^[3]

What options are left if two adequate treatments are insufficient?

A useful starting question is: Is there a benefit from the current treatment worth preserving?

If there has been no benefit or the side effects are significant, it may be reasonable to switch antidepressants. If there has been clear improvement and the medication is well tolerated, it may make more sense to keep what helps and add another intervention. That could be psychotherapy or, in selected cases, a medication. In augmentation, another treatment is added to reinforce the effect of the first. The clinician should explain the benefit they are aiming for, the added risks, and how they will monitor them. Augmentation has a specific purpose beyond prescribing “something stronger.” ^[5]

Psychotherapy has a role before medication options are exhausted

In the UK CoBalT trial, 469 adults in primary care remained depressed despite taking antidepressants for at least six weeks. At six months, 46% of people who added cognitive behavioral therapy to usual care saw their symptoms fall by at least half, compared with 22% with usual care alone. The trial measured response rather than full recovery, and it did not require everyone to have tried two adequate antidepressant courses. Within those limits, it answers a practical question. When medication alone is insufficient, psychotherapy can be part of the next step. ^[6]

When might specialized treatment be considered?

Repetitive transcranial magnetic stimulation is a noninvasive option in selected cases that have not responded sufficiently. Electroconvulsive therapy (ECT) may be considered in severe depression when other treatments have not worked or a rapid response is needed, for example if someone has stopped eating or drinking to the point that their health is at risk. In that situation, waiting to complete a list of medication trials makes little sense. The decision requires specialized assessment and an individual explanation of benefits and risks, including possible effects on memory with ECT. ^[5]

Intranasal esketamine illustrates another distinction. In the European Union it is authorized, in combination with certain oral antidepressants, for adults whose moderate or severe depressive episode has not responded to at least two different antidepressant treatments. It is administered under healthcare supervision. A diagnosis of treatment-resistant depression does not make esketamine mandatory or guarantee that it will be publicly funded. Spain’s October 2026 reimbursement listing sets out narrower criteria, including a current severe episode, age 18 to 74, and failure to respond to three strategies, including at least one combination or augmentation strategy. The clinical definition, authorized indication, and reimbursement requirements are separate questions. ^{[7] [8] [9]}

Related reading: Advanced treatments for treatment-resistant depression.

What to bring to a second opinion for depression

What often helps most is a timeline that shows how each decision was made. If you have reports, prescriptions, or a list, you can summarize each trial in a single line:

Medication or psychotherapy → approximate date and duration → dose, if you remember it → what improved → what problem came up → why it changed.

For example: “With the second treatment I stopped waking up in the middle of the night and started eating regularly again. I still didn’t feel like seeing my friends. We stopped because it made me dizzy, even though it had helped.”That gives more direction for the next decision than saying, “I’ve already tried everything.” Guidelines recommend considering prior response, tolerability, and preferences when choosing the next treatment. ^[5]

You do not need to remember every dose or delay the appointment until you find every report. Do not stop medication just to be evaluated off treatment. An unplanned discontinuation can cause symptoms and make the assessment harder to interpret. ^[3]

In a second opinion, I would want you to leave with three clear answers: which treatments we know have been insufficient, what information is missing, and what a reasonable next step looks like. Sometimes that means changing course. Sometimes it means preserving hard-won improvement while addressing the problems that remain. In either case, I would agree with you on when to review the outcome and which signs would warrant an earlier appointment.

Have you tried several treatments and feel unsure what to do now?

You do not need to know in advance whether your depression is treatment-resistant. You can seek an assessment with a more specific question: “Here is what I have tried. Here is what I still can’t do. What should we review before making another change?”.

Dr. Marc Agraz · Psychiatry in Lleida and online. Assessment of diagnosis, course, and prior treatments, with referral to a specialized service when appropriate. Scheduled consultations do not provide emergency care. ^[11]

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