Treatment-resistant depression: the order I try things in, including Spravato

Treatment-resistant depression has a specific definition in psychiatry: a major depressive episode that has not responded adequately to at least two antidepressant trials of adequate dose and duration. About a third of patients treated for depression end up in this category, which means it is not rare and it is not a sign that the patient has done something wrong. It does mean that the standard sequence of trying one antidepressant after another has stopped being the best plan. Here is the order in which I work through the alternatives, and why.

Step zero: make sure it is treatment-resistant depression

Before I call a depression treatment-resistant, I confirm that the prior trials were real. Many patients referred to me have taken three or four antidepressants, each for a few weeks at a starting dose, or each stopped because of early side effects. Those are not failed trials; they are incomplete ones. An adequate trial means a therapeutic dose for at least six to eight weeks with reasonable adherence.

I also recheck the diagnosis. Bipolar depression does not respond well to antidepressants and often gets worse on them. Depression with psychotic features needs an antipsychotic alongside the antidepressant. Untreated sleep apnea, hypothyroidism, alcohol use, chronic pain and certain medications can keep a depression going no matter what is prescribed for it. I order laboratory work, review the history for periods of elevated mood and ask about substances before I move forward.

Step one: optimize what is already there

If the current antidepressant has produced partial benefit, I push it to the top of its dose range before I abandon it. This is the least disruptive move and it is skipped more often than it should be. I also address sleep, alcohol and physical activity directly, because each of them has a measurable effect on depression and each is under at least partial control of the patient.

Step two: switch

If the current medication is doing little, I switch to one from a different class. STAR*D, the largest antidepressant study ever conducted, showed that switching within a class and across classes produced similar results on average, so I let the patient's side-effect history and symptom pattern decide. For some patients at this stage I consider older agents that are underused today: tricyclics such as nortriptyline, which have stronger evidence in severe depression than many people realize, and monoamine oxidase inhibitors, which can work when nothing else has, provided the patient can manage the dietary and drug restrictions.

Step three: augment

Augmentation means adding a second medication to an antidepressant that is partly working. The options with the strongest evidence are:

• Aripiprazole, brexpiprazole, quetiapine and cariprazine, second-generation antipsychotics that are FDA-approved as add-on treatment for major depression. They work within weeks but carry metabolic and movement side effects that require monitoring.
• Lithium, which has decades of evidence as an augmenting agent and a specific protective effect against suicide. It requires blood level monitoring and kidney and thyroid checks.
• Bupropion, often added to an SSRI, which also helps with fatigue and sexual side effects.
• Thyroid hormone, specifically triiodothyronine, which performed comparably to lithium in STAR*D with fewer side effects.

I choose among these based on the patient's other symptoms, weight, cardiac history and willingness to do laboratory monitoring. I do not stack more than one augmenting agent without a clear reason, because polypharmacy is where side effects multiply and clarity disappears.

Step four: Spravato

Spravato (esketamine) nasal spray was approved by the FDA in 2019 for adults with treatment-resistant depression, originally alongside an oral antidepressant and more recently as a standalone treatment as well. It works differently from every medication above. Rather than acting on serotonin or norepinephrine, it acts on the glutamate system, and its effects can appear within hours to days rather than weeks. For a patient who has done steps one through three properly and is still seriously depressed, this is the point at which I bring it up, and I bring it up directly, because many patients have never been offered it.

The Boynton Beach office is a certified Spravato treatment site, which matters for a practical reason: Spravato cannot be taken at home. The FDA requires that it be administered in a certified clinic under a risk evaluation and mitigation strategy. Here is what the treatment involves:

• Each dose is self-administered as a nasal spray in the office, with a staff member present.
• The patient is monitored for about two hours afterward. Blood pressure is checked before and after, because esketamine can raise it temporarily. Dissociation, a feeling of detachment or altered perception, is common during the first hour and fades.
• The patient cannot drive until the next day and needs a ride home.
• The induction phase is twice weekly for four weeks. If the patient responds, treatment continues weekly for the next month and then weekly or every other week based on how they are doing.

I evaluate every candidate for Spravato in person. I review blood pressure history, past or current substance use, any history of psychosis and the patient's capacity to commit to the schedule. I also keep the oral antidepressant and the rest of the plan in place; Spravato is an addition to careful treatment, not a replacement for it.

Step five: TMS

Transcranial magnetic stimulation is an FDA-cleared treatment that uses magnetic pulses to stimulate the part of the brain involved in mood regulation. It requires daily sessions for several weeks, involves no medication and no anesthesia, and has a low side-effect burden. I place it alongside Spravato rather than strictly after it. For a patient who wants to avoid further medication, who has had trouble tolerating drugs or who cannot arrange the ride home that Spravato requires, TMS may be the better fit, and I refer within Stedfast Psychiatry.

Step six: electroconvulsive therapy

ECT remains the most effective treatment for severe depression, with response rates higher than any medication, and it is the treatment of choice when depression is life-threatening, when a patient has stopped eating or drinking, or when psychotic features are present. Modern ECT is done under anesthesia with muscle relaxation, and the main side effect is temporary memory disruption. I discuss it honestly when it is the right option and refer to a hospital program that provides it.

Psychotherapy throughout

At every step, psychotherapy stays in the plan. Cognitive behavioral therapy and behavioral activation have evidence in treatment-resistant depression specifically, and combining therapy with medication outperforms either alone. A patient who has been depressed for years has usually built habits, beliefs and avoidance patterns around the illness, and medication alone will not dismantle them.

What I tell patients at the start

I tell patients with treatment-resistant depression that the name is misleading. The depression has resisted the treatments tried so far, not all treatment. The options I have described are real, they have evidence behind them and most patients who work through them in order find something that helps. The work is to be systematic about it, to give each step a fair trial and to measure the result rather than guess at it. That is what I do, and it is why I put the order in writing for every patient at the first visit.

More from Dr. Gobar

• How I think about changing an antidepressant that has stopped working2026-06-10
• Psychosis is treatable: what I tell families at the first visit2026-07-08
• Work stress or something more: how I tell the difference2026-08-05

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