Most cases labeled as treatment-resistant depression never completed the first step of treatment. Before ketamine, ECT or TMS, it's worth knowing where you stopped.
“I have tried everything. Nothing works.”
It is the sentence I hear most often from people who come to me after years of living like this. It arrives with a list — four, five, six drug names, some remembered by heart, others on a creased piece of paper — and with a conclusion the person had already reached as final before sitting down: I am a lost cause.
Many of these people arrive with a second thing on their mind. They have heard about ketamine, about transcranial magnetic stimulation, about electroconvulsive therapy. They have read that these are revolutionary. Sometimes someone has already offered one of them.
In my experience, the great majority of these people are not treatment-resistant. They have never actually completed, properly conducted, the first step of the treatment indicated for them.
Perhaps that describes something of your own history. Or perhaps you are researching these treatments right now, for yourself or for someone close to you. Either way, it is that distance I wanted to talk about: the distance between having tried a great deal and having been treated.
Two words that look the same and are not
Refractory depression — the more current term is difficult-to-treat depression — describes an illness that does not respond after adequate, well-conducted attempts. The key word here is adequate. Treatment resistance is a diagnosis that can only be made after treatment has been done properly, and has not worked.
What I see far more often is something else, and it deserves its own name: pseudo-resistance. It is the person labeled resistant who, when you look calmly at the history, never had an adequate treatment to call a failure. Plenty of medications tried, yes — but none of them as they should have been.
The difference between the two scenarios is not subtle. One leads to increasingly complex and expensive interventions. The other is often resolved by going back and redoing the beginning.
Where things usually go off course
When I say that the treatment was not adequate, this is not a criticizm of anyone who tried before — neither the patient nor the colleague. It is a technical observation about what tends to be missing.
The diagnosis has to be right before the first prescription is written. One example changes everything: a meaningful share of the depressions that “do not respond” are in fact bipolar spectrum conditions — and then the path is a different one, and persisting with the first can make things worse. Screening for this before prescribing is not a detail; it is the foundation.
The dose has to reach a therapeutic level, rather than stopping at the first one that produced some side effect.
The time has to be sufficient. Real improvement usually takes weeks. Treatment abandoned or switched too early is not treatment that failed — it is treatment that never happened.
And none of this means anything without measurement. Following the response with a scale, rather than by the impression of the day, is what separates clinical management from guesswork.
Subtract any one of these and you have an “attempt” that, on paper, thickens the list of failures, but that clinically was never a fair test. Multiply that by five or six medications over the years, and what is born is an “I have tried everything” that is true in your experience and false in technical terms.
There is a map — and it is not guesswork
One of the things that most reassures someone who believes they are a lost cause is discovering that the treatment of depression is not trial and error in the dark.
There is a structured pathway, evidence-based and organized by international guidelines — I work from the Canadian CANMAT guideline, adapted to each person. That pathway has an order to it: careful assessment before prescribing, a well-conducted and measured first line, a formal reassessment at a defined interval, and only then the subsequent steps, when they are genuinely indicated.
Recently I laid out the full algorithm of that pathway to show a patient exactly where she was. She had arrived convinced she was treatment-resistant, asking about ketamine. On the flowchart you could see it with the naked eye: she had barely left the first stage.
What was missing was not a more powerful treatment. What was missing was finishing what had already been started — and never completed.
I deliberately do not reproduce doses or medication names here: that is an individual clinical decision, made in the consultation, and not blog material. What matters to the reader is the shape of the path. And the shape says something uncomfortable: most people who have “tried everything” are, in fact, stuck somewhere near the beginning.
Ketamine, ECT and TMS: the problem is not what they are
Here I need to be very precise, because it is easy to read what follows as if I were turning my nose up at these tools. I am not.
Ketamine, electroconvulsive therapy and transcranial magnetic stimulation are legitimate resources, with solid evidence behind them, and in the right cases they make a difference no tablet makes. Depression is not a purely monoaminergic phenomenon — it is also glutamatergic and neuroplastic, and these interventions reach mechanisms that conventional antidepressants do not reach. An anesthetist colleague who has worked with ketamine for years once said to me, quite rightly, that there is still a shortage of knowledge and of nerve when it comes to offering it to the people who genuinely need it. I agree with him.
The problem is not what these interventions are. It is how they reach you.
They tend to be presented as the last hope — and often as the only one. This happens by different routes. Sometimes it is a well-meaning professional from outside psychiatry who hears “the medications did not work” and concludes, understandably but mistakenly, that the case has exhausted the conventional options. Sometimes it is the person themselves who searches, finds enthusiastic promises online, and arrives asking for one of them by name.
None of these interventions is the only hope. All of them have limitations, costs and precise indications. And none of them was designed to replace a stage that was never carried out.
The question was never whether they work. It is where they belong in the pathway. Offering an advanced-line intervention to someone who has not yet completed the basic line is not therapeutic boldness — it is skipping a stage that would often have resolved things, at a human and financial cost that did not need to exist.
Why this is, underneath everything, good news
If you recognized yourself in this text — if you carry the label of treatment-resistant and the feeling of having exhausted everything — what I have to say is less bleak than years of frustrated attempts have led you to believe.
“Treatment-resistant” is, in an enormous number of cases, a reversible label. Not because there is a magic cure or an easy promise — there is not, and anyone promising that is lying. But because when the assessment starts again from scratch and the first step is finally conducted as it should be, a large proportion of the people who “responded to nothing” begin to respond. Often before any expensive or invasive intervention.
This is not true for everyone. Genuine treatment resistance exists, and those who are truly in it deserve exactly those advanced resources, at the right point in the pathway. But it can only be asserted after the pathway, not before it.
And that is why the most useful question, for someone who arrives saying “I have tried everything”, is almost never “what is the next, stronger treatment?”. It is another one:
“Of everything you have tried, what actually amounted to a treatment?”
You do not have to conclude anything today
There is nothing to decide right now, and no need to convince yourself that the previous years were wasted — they were not, and reading them that way would not help at all.
Perhaps just keep hold of this: before accepting that nothing works for you, and before moving on to an expensive intervention, it is worth knowing exactly where you stopped along this pathway. It is a question you answer with someone, looking calmly at the whole history — not alone, rereading the list of medications.
Perhaps you never reached the end of the beginning.
Related reading
- The difference between being sedated and being treated
- What accelerates (and what delays) the response to an antidepressant — the role of psychiatric management
- Are antidepressants addictive? The fear that leads to taking less than you need
Do you feel you’ve already tried everything against depression?
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Dr. Leonardo Sodré is a psychiatrist and psychotherapist in Brasília, Brazil (CRM-DF 14.206 · RQE 14.761). He holds a PhD in Psychiatry from UFRGS and teaches at the University of Brasília School of Medicine. This content is informative and educational and does not replace individual assessment, diagnosis or treatment.