When depression doesn't get better

Many people feel better with the first or second treatment they try for depression. But some do not. If you have tried treatment and still feel low, tired or hopeless, you are not alone. It does not mean you are weak, and it does not mean nothing will work.

Doctors sometimes call this treatment-resistant depression. This page explains what that term means, what to check first, and the next steps doctors can offer.

What "treatment-resistant" means

There is no single official definition. Doctors often use the term when depression has not improved enough after at least two antidepressants, each taken long enough and at a full dose. Some prefer the gentler term "difficult-to-treat depression."

The U.S. veterans' health guideline (from the VA and Department of Defense) suggests judging a first medicine after about 4 to 6 weeks at a full dose. If there is only partial or no improvement by then, it is time to talk about a change.² The same guideline suggests treatments such as TMS after two or more full medicine trials have not worked well enough.²

Hope in the numbers. A large U.S. study called STAR*D followed thousands of adults through up to four treatment steps. About 37 in 100 people reached remission (being mostly free of symptoms) on the first medicine. About 31 in 100 of those who moved to step two got well there. Fewer did at steps three and four (about 13 to 14 in 100). The researchers estimated that about two out of three people could reach remission if they stayed with treatment through all the steps.¹

The study also found that people who needed more steps were more likely to have symptoms come back later.¹ This is one reason doctors often continue treatment after people feel well.

First, check the basics

Sometimes depression seems "resistant" when something else is in the way. Your doctor may go over these questions with you:

• Is the diagnosis right? Bipolar disorder can look like depression, and it needs different medicines. See bipolar disorder. Thyroid problems, low vitamin B12, sleep apnea and some medicines can also cause or worsen low mood. See getting checked for depression.
• Was the trial long enough and strong enough? A medicine needs several weeks at a full dose before you can judge it.²
• Was it taken every day? Side effects, cost or forgetting can get in the way. Tell your doctor the truth. It helps them plan.
• Is something else adding to it? Alcohol, pain, loneliness, grief, money stress or a medical illness can keep depression going. See depression with physical illness and alcohol and older adults.
• Is therapy part of the plan? For depression that is severe, long-lasting or keeps coming back, the VA/DoD guideline suggests combining medicine with a proven talk therapy.² See CBT and behavioral activation.

A simple symptom score, such as the PHQ-9, filled out every few weeks, can show whether you are really improving. Ask your doctor to track it with you.

Switching, adding and combining medicines

If the first medicine did not help enough, there are several paths. The VA/DoD guideline lists them as reasonable choices, without ranking one above the others:²

Newer add-on approval. In November 2025, the FDA added a new use for lumateperone (Caplyta). It can now be added to an antidepressant for adults with major depression.⁷ In studies, the most common side effects were headache, dizziness, dry mouth, sleepiness and nausea.⁷

Like all antipsychotic medicines, it carries the FDA's strongest warning, called a boxed warning. Older adults with dementia-related psychosis have a higher risk of death when taking these medicines.⁷ Older adults should ask about this, and about falls and drowsiness, before adding any antipsychotic.

Some doctors also add lithium or another medicine. Which choice is best depends on your health, your other medicines and what side effects you can live with. See antidepressant medicines.

TMS (transcranial magnetic stimulation)

TMS uses a magnet placed against the scalp to send gentle, repeated pulses to a part of the brain involved in mood. You stay awake. No anesthesia (medicine to put you to sleep) is needed, and you can usually go back to your day afterward.³

• How it is given: In a clinic, usually 5 days a week for 4 to 6 weeks. Each session lasts from a few minutes to about 40 minutes.³
• Faster schedules: Newer "accelerated" forms give several sessions in one day. They can work in about a week for some people.³
• Side effects: Scalp discomfort, muscle tingling or twitching, mild headache and lightheadedness. Seizures can happen but are rare.³
• FDA status: The first TMS device was cleared in 2008 for adults whose depression did not improve with an antidepressant.³

The VA/DoD guideline suggests TMS after two or more medicine trials have not worked well enough.² Moderate evidence Read more on our brain stimulation page.

ECT (electroconvulsive therapy)

ECT may sound frightening because of old movies. Today it is done very differently. You are fully asleep under brief general anesthesia and given a muscle relaxant. A small electric current causes a short seizure in the brain, lasting less than a minute.³

• How often: Usually three times a week until symptoms improve, often about 6 to 12 treatments in total. Some people then have less frequent "maintenance" sessions.³
• Side effects: Headache, upset stomach, muscle aches, confusion right after treatment, and memory loss. Memory problems usually improve over days to weeks.³
• Who it is for: Severe depression that has not responded to several medicines, or when a fast response is needed, such as when a person is at high risk of suicide.^2,3

ECT is the only treatment on this page that the VA/DoD guideline gives a strong recommendation for in severe depression after poor response to several medicines.² Strong evidence

Esketamine nasal spray (Spravato)

Esketamine is a medicine made from ketamine. It comes as a nasal spray called Spravato. It is FDA-approved for adults with treatment-resistant depression, either alone or with an antidepressant pill. It is also approved, with an antidepressant pill, for adults with depression who have current suicidal thoughts or actions.⁴ Moderate evidence

How it works in practice. You cannot take it home. As of October 2026, it is given only in certified clinics. You spray it yourself while a health worker watches.⁴ Then you stay at the clinic for at least 2 hours so staff can watch for side effects.⁴ You need someone to drive you home. You should not drive until the next day after a good night's sleep.⁴

Schedule. Treatment usually starts twice a week for the first 4 weeks. Then it drops to once a week for 4 weeks. After that, it is once a week or every 2 weeks, using the least frequent schedule that keeps you well.⁴

Side effects. In studies of people with treatment-resistant depression, common side effects included:⁴

Source for the table: FDA label for Spravato.⁴

The label also has a boxed warning about sedation, breathing problems, dissociation, and the risk of misuse.⁴ People with certain blood vessel problems, such as an aneurysm, or a past bleed in the brain should not use it.⁴

What older adults should know. In a 4-week study of adults 65 and older, esketamine did not do better than a placebo (a look-alike with no medicine) by a clear, statistically significant amount.⁴ Older adults in that study also had more sleepiness and bigger jumps in blood pressure than those on placebo.⁴ An older person should talk carefully with the doctor about likely benefit, blood pressure and fall risk.

Ketamine

Ketamine has been FDA-approved as an anesthetic for many years.⁶ Some clinics give it in low doses through an IV (a drip into a vein) for depression. This use is not FDA-approved for depression. Only esketamine has that approval.⁶

There is good research behind IV ketamine, though. A 2023 U.S. study compared IV ketamine with ECT in 403 adults with treatment-resistant depression who did not have psychosis. After about three weeks, about 55 in 100 people improved a lot with ketamine, compared with about 41 in 100 with ECT.⁵ Short-term memory scores dropped more with ECT, then slowly recovered. Ketamine more often caused a brief disconnected feeling.⁵ Moderate evidence

Some things to keep in mind:

• The VA/DoD guideline suggests ketamine or esketamine as an add-on option after several medicine trials have not worked.²
• IV ketamine is often not covered by insurance, so costs can be high. Ask before you start.
• Ketamine can be misused, and it changes how you sense reality for a while.⁶ Choose a clinic run by doctors who will check your heart, blood pressure and full medical history.
• Avoid ketamine products sold for unsupervised use at home unless your own doctor is closely involved.

Read more on our ketamine and esketamine page.

Other treatments

Vagus nerve stimulation (VNS). A small device is placed under the skin of the chest. A wire sends mild pulses to a nerve in the neck. The FDA approved it in 2005 for adults with long-lasting depression that has not improved after at least four treatments. It is used rarely, benefits can take months, and study results are mixed.³ Limited research

Deep brain stimulation (DBS). This involves brain surgery to place wires deep in the brain. For depression, it is still experimental and offered only in research studies.³ Limited research

Psilocybin and other psychedelics. These are being studied for hard-to-treat depression. The VA/DoD guideline strongly advises against psilocybin outside of a research study, because there is not yet enough information on safety and benefit.² Promising See psychedelic research.

How to find the right specialist

If two or more treatments have not worked well, ask your primary care doctor for a referral to a psychiatrist (a medical doctor who specializes in mental health). Some places have special "mood disorders" or "treatment-resistant depression" clinics, often at university hospitals.

1. Ask your doctor: "Could this be treatment-resistant depression? Who can see me next?"
2. Bring a list of every antidepressant you have tried, roughly how long, and what happened. A memory notebook can help.
3. Ask if the clinic offers TMS, esketamine or ECT, or can refer you to a place that does.
4. Search for mental health providers near you at FindTreatment.gov, a free and private tool from the U.S. government's mental health agency (SAMHSA).⁹
5. Call your insurance or Medicare plan to ask what is covered and what you will pay.

Medicare. Medicare Part B covers outpatient mental health care, including visits with a psychiatrist and other mental health providers, medicine management and therapy. After the Part B deductible, you usually pay 20% of the Medicare-approved amount.⁸ Coverage for TMS, ECT and esketamine can depend on your plan and whether certain conditions are met, so check before you start. See Medicare and mental health and paying for therapy.

If English is not your first language, ask for a free medical interpreter at every visit.

When to get help right away

Depression that lasts a long time can wear down hope. That is the illness talking, not the truth about your future. Many people who struggled for years do find a treatment that works.

If you are helping a loved one, see helping someone with depression. For the full picture, go back to the depression overview, treatment for depression or depression in later life.

Education only. This page is general information written from the sources listed. It is not medical, legal or financial advice and does not replace a doctor, therapist or lawyer who knows your situation. How we write and check pages.