Cornerstone guide 02

The approved next-line treatments

By the editorial team - Reviewed for plain-language accuracy

When two antidepressants have not worked, the conversation shifts. Instead of simply cycling through more pills of the same type, clinicians can turn to a set of next-line treatments, several of which are FDA-approved and specifically studied in people with treatment-resistant depression. Here is a plain-language tour of the main options. None of this replaces a conversation with your own clinician, but knowing the landscape makes that conversation far more useful.

Esketamine (Spravato)

Esketamine is a nasal spray derived from ketamine, and it is FDA-approved for treatment-resistant depression in adults, used alongside an oral antidepressant. It works on a different brain system than standard antidepressants, targeting glutamate signaling, which is one reason it can help people who did not respond to the usual medications.

Because of how it works, esketamine is given in a certified medical setting. You take the spray under supervision and stay for monitoring afterward, usually about two hours, because it can cause temporary dizziness, dissociation, or a rise in blood pressure. That structure is a safety feature, not a red flag. For some people, improvement can begin sooner than it typically does with oral antidepressants, though responses vary a great deal from person to person.

Transcranial magnetic stimulation (TMS)

TMS uses focused magnetic pulses to stimulate a region of the brain involved in mood regulation. It is FDA-cleared for depression that has not responded to medication, and it does not require anesthesia or a hospital stay. You sit in a chair, awake, while a device delivers pulses to the scalp over the target area.

A typical course runs over several weeks, with sessions on most weekdays, each lasting anywhere from a few minutes to around forty, depending on the protocol. The most common side effect is scalp discomfort or headache near the treatment site, which usually eases over time. Because it is drug-free, TMS can appeal to people who cannot tolerate medication side effects.

Medication strategies

Not every next step involves a new device or setting. Clinicians also use two medication approaches. "Augmentation" means adding a second medication to boost the one you are already taking. "Combination" means pairing antidepressants that work in different ways. In some cases a doctor may add a low dose of a medication from another class to strengthen the effect. These strategies are well established and are often tried alongside or before the more specialized options.

Therapy, still part of the plan

Structured talk therapies, such as cognitive behavioral therapy, remain a core part of care even when medication has not been enough. Therapy is not a consolation prize. For many people the strongest results come from pairing a biological treatment with an evidence-based therapy, because the two address different parts of the problem.

Other options for severe cases

For severe or urgent depression, particularly when a fast response is critical, treatments like electroconvulsive therapy (ECT) remain among the most effective available and are delivered in specialized settings. These are decisions made carefully with a psychiatric team, and they are worth knowing exist.

The right choice depends on your history, your other health conditions, what you can tolerate, and what is available near you. There is rarely a single obvious answer, which is why a thoughtful clinician matters as much as the menu of options. The next guide covers what to realistically expect once you begin.

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