TREATMENT-RESISTANT DEPRESSION
“Treatment-resistant depression” is a label about the treatments
Not about you. It has a real clinical definition, and most people who meet it have never been told they do. Here is what it actually means, and what the four serious options are once you qualify.
2Failed trials is the threshold
70%Average PHQ-9 drop
6Infusions over 2–3 weeks
Symptom-score data based on AlphaOmega Wellness treatment records, 2022–2026, using PHQ-9 and GAD-7. Individual results vary.
WHAT IT ACTUALLY MEANS
Two adequate trials. That is the bar.
Treatment-resistant depression means depression that has not responded to at least two adequate trials of antidepressant medication. Adequate is doing real work in that sentence — it means a proper dose, taken for a proper length of time, usually six to eight weeks.
If you have been through two of those and you are still here, you meet the definition. That is roughly a third of everyone treated for depression, and almost none of them have been told the label applies to them.
It is worth saying plainly: this is a statement about what those particular medications did. It is not a statement about how treatable you are.
ONCE YOU QUALIFY
The four real options, side by side
This is the question every treatment-resistant patient is actually asking, so here is the honest version rather than the version that only flatters us.
IV ketamine
Six infusions over two to three weeks. Fast, often within days. Used off label, so it is self-pay.
Spravato
Esketamine nasal spray, FDA-approved specifically for TRD. Frequently covered by insurance.
TMS
Magnetic stimulation, usually daily for about six weeks. Non-invasive and often covered.
ECT
Still the most effective treatment in psychiatry for severe depression, and the most involved.
We laid all of them out properly, including at-home ketamine, on the comparison page. If one of the others is the better fit for you, we would rather you knew that now.
FIFTEEN YEARS
What carrying the label looks like
This is a husband describing fifteen years of watching his wife cycle through treatments that did not hold. If you have been at this long enough that people have stopped asking how you are doing, this one is worth four minutes.
More on the reviews page.
WHY A DIFFERENT SYSTEM
The reason two failures do not predict a third
Both of the antidepressants that did not work for you were almost certainly working on the same system: serotonin, slowly, over weeks. A third drug from the same family is a third roll of the same dice.
Ketamine acts somewhere else — glutamate and the NMDA receptors, which triggers BDNF and helps rebuild synaptic connections that chronic depression wears down. That is why a history of failed SSRIs does not predict how you will respond to this, and why treatment-resistant depression is the population ketamine has its strongest evidence in.
The protocol step by step is on the IV ketamine therapy page.
Struggling with suicidal thoughts? If you are in crisis right now, call or text 988. When you are safe, know that ketamine has strong, fast-acting evidence for reducing suicidal ideation, and we are here to help.
QUESTIONS PEOPLE ACTUALLY ASK
Treatment-resistant depression and IV ketamine
How do I know if I am treatment-resistant?
If you have completed at least two adequate trials of antidepressant medication — proper dose, six to eight weeks each — without an adequate response, you meet the clinical definition. Bring your medication history to the consult and we will go through it with you.
Does a history of failed antidepressants mean ketamine will fail too?
No, and this is the important part. Those medications work on serotonin. Ketamine works on glutamate. Failing one says very little about the other, which is why treatment-resistant depression is the group with the strongest evidence behind IV ketamine.
Should I try Spravato instead?
Possibly, and we will say so if we think it. Spravato is FDA-approved for treatment-resistant depression specifically and insurers often cover it, which can make it the more practical starting point. It is a different route, dose and setting from an IV infusion.
How fast would I know if it is working?
Most people who respond notice something within the first two or three infusions rather than at the end. If nothing has moved by the end of the induction series, we will tell you that honestly rather than sell you another round.
How many infusions, and then what?
Six over two to three weeks, then a reassessment. Some people need occasional maintenance and some do not. There is no forever schedule here.
Does insurance cover it?
No. IV ketamine for depression is used off label, so this is self-pay. HSA and FSA work, Affirm is available, and the full breakdown is on the cost page.
GET STARTED
Find out if this is a fit
Bring your medication history. A free consult runs about thirty minutes, with our team rather than a call center, and you will leave knowing whether IV ketamine is a reasonable next step — or which of the other three we would point you toward instead.
Medically reviewed by Dr. Dee Bonney, MD, board-certified emergency medicine physician, and Megan Bonney, PMHNP-C, board-certified psychiatric mental health nurse practitioner. AlphaOmega Wellness is physician-led and family-owned, in Greenwood, Indiana. Meet the team.