Let's Talk About Treatment-Resistant Depression

Sometimes depression doesn't respond to standard treatments, but that doesn't mean there's no hope. Here's where to find it.

by Denise Mann Health Writer

You’ve been struggling with feelings of sadness and hopelessness for as far back as you can remember, and the “miracle” medications that gave your best friend her life back don’t seem to be having the same effect on you. It’s been weeks since you started your latest antidepressant and you still feel the same—maybe even a little bit worse.

Treatment-Resistant Depression

Our Pro Panel

We went to some of the nation’s top depression experts to bring you the most up-to-date information possible. Look who’s on your side:

James W. Murrough, M.D., Ph.D.

James W. Murrough, M.D., Ph.D.

Director of the Depression and Anxiety Center for Discovery and Treatment and Associate Professor of Psychiatry and Neuroscience

Icahn School of Medicine at Mount Sinai

New York

Adam Kaplin, M.D., Ph.D. headshot.

Adam Kaplin, M.D., Ph.D.

Assistant Professor of Psychiatry and Behavioral Sciences Clinical Director

Johns Hopkins Medicine


Subhdeep Virk, M.B.B.S. headshot.

Subhdeep Virk, M.B.B.S.


The Ohio State University Wexner Medical Center

Columbus, OH

Treatment-Resistant Depression
Frequently Asked Questions
How common is treatment-resistant depression?

Up to 30% of people with depression have treatment-resistant depression, meaning that they haven’t gotten better after trying at least two antidepressant medications for an appropriate length of time and in an adequate dose.

How is a treatment-resistant depression diagnosis made?

Your doctor will evaluate you on an ongoing basis to see whether your medications are working. If you don’t feel significant improvement after trying at least two different medications, you’re likely to be diagnosed with treatment-resistant depression. Your doctor may also base the diagnosis on your responses to depression scales and questionnaires.

What medications are available for treatment-resistant depression?

There are many medications that your doctor can prescribe, along with therapy, to help you recover from your depression. In addition to standard antidepressants, doctors are excited about ketamine, a new way to approach depression that works in hours as opposed to weeks.

What is it like to have treatment-resistant depression?

Besides all the other emotions of depression, you might also feel frustrated and hopeless after trying medication after medication and not feeling any better. With treatment-resistant depression, depression symptoms, including hopelessness, sadness, anxiety, and even having suicidal thoughts, tend to worsen. But even though you haven’t found the right treatment yet, it’s important to keep trying all forms of help that might get the response you’re looking for.

Your doctor added another medication to the mix, and again...nothing. With each failed treatment, you’re growing more discouraged and you’re worried about the damage your depression is doing to your relationships and your career. Turns out, you’re experiencing what doctors call “treatment-resistant depression,” but does that mean you’re destined to be resistant to treatment indefinitely?

The answer to that question is a resounding no. There is light at the end of this tunnel. There are more treatments than ever before, so there’s a good chance you’ll find a treatment or combination of treatments that gets you back to being you. Here’s everything you need to know about treatment-resistant depression.

What Is Treatment-Resistant Depression Anyway?

There’s no one universally agreed upon definition for treatment-resistant depression yet (researchers are getting closer to one), but you don’t need a textbook to know that you’re not feeling better. If you’ve tried at least two antidepressants at a strong enough dose and for an appropriate length of time and haven’t responded, your depression may be considered treatment-resistant.

There are a lot of variables when it comes to finding medication success. You might have tried two medications from the same or from different classes of antidepressants. On average, you need about six to eight weeks to tell if an antidepressant is going to work for you.

When you check in with your doctor to discuss whether (or how well) your treatment is working for you, he or she may use a number scale to see if your symptoms are improving or may ask you to answer questionnaires on your symptoms. If your symptoms have decreased by at least half of what they were when you started a medication, you’re getting better.

The scales (and there are many of them out there) are pretty clinical, and sometimes it just boils down to something as simple as “Do you feel any better?” But for many people, the answer is no. About one-third of those living with depression have treatment-resistant depression, according to results from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study funded by the National Institute of Mental Health in Bethesda, MD.

Get the Full Story on Depression

Why Do Some People Experience Treatment-Resistant Depression?

No one knows why some people with depression get better and others don’t. If you have a history of trauma or abuse, you may be less likely than others to respond to antidepressants.

Researchers have also found that people with treatment-resistant depression have relatively high levels of inflammatory markers in their blood, including C-reactive protein. Brain imaging scans have shown shrinkage in certain areas that control emotional regulation such as the prefrontal cortex and hippocampus. Your depression may also be harder to treat if you’re living with another chronic medical condition.

There are other reasons you may not be responding to your treatment: Your original diagnosis could be wrong. It’s possible that your symptoms are caused by bipolar disorder or another condition—not depression—which would explain why the treatments aren’t easing your symptoms. The dose could be off as well. Sometimes, and for a laundry list of reasons, you may not be taking your medication as directed—maybe the side effects are too bothersome or perhaps it’s the cost of the drugs.

What Are the Symptoms of Treatment-Resistant Depression?

Treatment-resistant depression shares the same symptoms as depression, but because they don’t get better with treatment, they tend to grow more severe. You’re likely to experience:

  • Overwhelming sadness that’s not related to a recent event, like the loss of a loved one

  • Crying for no obvious reason or struggling to hold back tears

  • Heart-racing worry and panic with no real trigger

  • Having no interest in activities and pastimes that you used to be passionate about

  • Utter exhaustion that makes it hard to get out of bed

  • Eating close to nothing—you’ve lost the taste for foods you used to crave and are losing weight or, conversely, eating everything in sight and gaining weight

  • Feeling like you can’t or don’t want to go on, even if you have loved ones who need you

  • Thinking the world wouldn’t miss you if you ended it all and even how you might do it

For a first diagnosis of depression, you need to have had such feelings and behaviors nearly every day for at least two weeks. With treatment-resistant depression, they are ongoing, and because of this, it's likely you’ll experience more suicidal thoughts than before. You’ll likely notice that other symptoms of depression seem to grow more severe with each failed treatment.

How Can You Manage Treatment-Resistant Depression?

There are more treatments available today than ever before to help you feel like yourself again. As hard as it might be to hear, it will still take time to see if a new treatment is successful.


It’s not unusual to not respond as well as you’d like to medication alone. In fact, many people prescribed antidepressants for depression don't respond fully. Though a common next step is to try another or add another medication (more on this to come), you may feel more comfortable and have a better response by adding psychotherapy to your treatment plan.

According to a Cochrane Review of research on psychotherapy’s benefits, there’s evidence that, when given in addition to antidepressants, people with treatment‐resistant depression see improvement in their symptoms and have a greater likelihood of remission rates over the short- and long-term.

The two approaches can work hand-in-hand: Medication can address the underlying chemical causes of your depression, while therapy allows you to recognize, change, and challenge behaviors that are making your depression worse—an approach called cognitive-behavior therapy or CBT is particularly effective at this. The research shows that these combinations result in fewer episodes of depression for individuals with a treatment-resistant form of the condition and that people are more likely to be symptom-free after six months when therapy is added to the mix.

There are many forms of therapy to consider, including the option to work one-on-one with a therapist or with a group of people going through what you’re going through. You can even do both.

Adding a Second Medication

The first treatment for depression is usually a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI). If you don’t feel better after taking an appropriate dose for the right length of time, your doctor may try another drug, even one in the same class, as there are nuances to each of these drugs.

However, once you don’t respond to two single antidepressants, your doctor may add a second medication to the mix. This may include an older antidepressant known as lithium or a second-generation antipsychotic such as:

  • Abilify (aripiprazole)

  • Geodon (ziprasidone)

  • Risperdal, Perseris, Risperdal Consta (risperidone)

  • Seroquel (quetiapine)

  • Zyprexa, Zyprexa Zydix, Zyprexa Relprevv (olanzapine)

There's also the option now to try Symbyax (olanzapine and fluoxetine HCl capsules)—the first drug approved by the Food and Drug Administration (FDA) for treatment-resistant depression, it combines an SSRI with olanzapine.

Your doctor may also consider adding synthetic thyroid hormone, even if your thyroid gland is functioning just fine. This is considered an off-label use, but there’s a growing body of evidence that suggests it can help lift the fog of depression.

As before, you should know within eight weeks if the new medication is working, but sometimes it takes longer to get the full benefits.

Other Treatments to Consider

If you have tried several antidepressants, therapy, and combinations and still feel weighed down by depression, there are other treatments to try in consultation with your doctor.

Electroconvulsive Therapy (ECT)

Forget what you think you know about ECT based on how it’s portrayed in movies such as One Flew Over the Cuckoo’s Nest. ECT, which uses an electric current to treat depression, is the gold standard for severe depression. The theory is that your brain is “stuck” in a negative pattern and needs a jolt to reset. Think of it the way that a defibrillator can reset an abnormal heart rhythm during cardiac arrest or atrial fibrillation.

ECT works and works well to treat severe depression. In fact, up to 90% of people will feel better after undergoing a series of ECT treatments, note researchers from Johns Hopkins Medicine in Baltimore. It’s also safe when performed in the right setting.

Treatments are done three days a week for two to three weeks; they’re performed in a hospital, either as an outpatient or an inpatient depending on your needs, while you’re under a short-acting anesthesia. The entire session, including time in the recovery room, is just an hour. If you get ECT as an outpatient, you’ll need someone to drive you home and be with you for the rest of the day—you may feel nauseous, headachy, or even have muscle aches for an hour or so.

Depending on how you respond, you may want to take it slow on days between sessions. And there’s no driving allowed for the following 24 hours. Some people experience problems with memory and thinking afterward, but these are usually not prolonged or permanent, according to the National Alliance on Mental Illness in Arlington, VA.

Transcranial Magnetic Stimulation (TMS)

Think of TMS as a lighter version of ECT. This treatment delivers an electrical current to the brain with a powerful magnet at a lower level than used with ECT. Treatment is given five days a week for several weeks in your doctor’s office, and each treatment lasts about 30 to 60 minutes. It’s non-invasive and doesn’t require anesthesia.

It also has fewer side effects than ECT. You may develop a headache or feel pain at the site of the stimulation, and sometimes there can be tingling, spasms, or twitching of facial muscles after treatment. As many as 60% of people with depression who have not improved with medications will respond to TMS and about one-third will experience a complete remission, Harvard Health reports. These results, however, are not permanent and maintenance sessions may help prolong the benefits. There are a few devices that have the FDA’s nod for treatment-resistant depression, including DeepTMS, Magstim, and MagVenture TMS Therapy.

Vagus Nerve Stimulation (VNS)

With this treatment, a small pulse generator roughly the size of a silver dollar is placed in the upper left side of your chest to stimulate your vagus nerve, the nerve tasked with carrying messages to parts of the brain that control mood and sleep. A wire is then threaded under the skin in your neck to connect the device to your vagus nerve. The battery-operated and pre-programmed device sends electrical pulses along the nerve to your brain when activated (you won’t feel these pulses).

First approved for people with epilepsy, patients who had epilepsy and depression reported that their depression symptoms also seemed to ease with VNS, and it was independently approved a few years later for treating treatment-resistant depression. You may not feel any benefits for the first few months. But up to 30% of people with the implant found improvement after a year.

Surgery to implant the device requires just two small incisions, one on the chest and the other on the lower neck, and takes at most 90 minutes, all while you are under general anesthesia. The battery can last up to 15 years. VNS may be an option if your depression hasn’t lifted after trying four different medications or ECT, but it’s not for people who are suicidal. Side effects may include hoarseness, swallowing difficulty, and neck pain, among others. Not all insurers will cover the cost of this treatment for depression, so it’s important to check your policy.

Deep-Brain Stimulation (DBS)

This treatment is best known for helping to alleviate some of the symptoms of Parkinson’s disease, but it may also play a role in hard-to-treat depression.

With this two-step surgical treatment, your surgeon implants two electrodes, one in the brain and the other in the chest. It’s akin to a pacemaker in your brain and is programmed and controlled from outside your body by a handheld device.

It’s still considered experimental for depression. Researchers are not 100% sure how it works, but it’s likely that the pulses reset connections in the brain. Study on DBS is ongoing, but for now it’s usually considered only if you haven’t responded to antidepressant medicines, talk therapy, and ECT.


There’s a lot of excitement about this drug being a game changer for treatment-resistant depression. The FDA-approved Spravato (esketamine) is a nasal spray that is an add-on treatment to an oral antidepressant (it can also be given intravenously). It’s the first truly novel medication to treat major depression in decades, and it does so in an entirely new way.

Unlike serotonin or norepinephrine, it doesn’t target monoamines or brain chemicals. It belongs to a class of drugs known as NMDA receptor antagonists, and the idea is that it may help regrow connections between brain cells that play a role in mood. It was once a widely known (and abused) club drug known as Special K and has been used for pain relief, too.

Ketamine works quickly, usually within a couple of hours, which is great news compared with oral antidepressants that can take weeks to help. About 70% of people with treatment-resistant depression who were started on an oral antidepressant and intranasal ketamine improved, compared to slightly more than half in the group that didn’t receive the medication, according to an UpToDate report.

The downside? The results are short-term—starting within a few hours but lasting only days. Also, Spravato must be given in your doctor’s office—you can’t take it on your own at home, and because it can cause temporary disorientation or confusion, you’ll need to stay there for a couple of hours after each treatment. It’s usually given twice weekly for the first month, and once a week for the second month. Beyond that, you might be able to scale down to once every two weeks, all while still taking an antidepressant.

Insurance will likely cover the cost if you’ve failed two prior treatments. Research is ongoing, with scientists working to develop ways to deliver it so that the effects will be long-lasting and trying to learn more about any long-term side effects.

Denise Mann
Meet Our Writer
Denise Mann

Denise Mann, MS is a veteran freelance health writer in New York. Her work has appeared on HealthDay, among other outlets. She was awarded the 2004 and 2011 journalistic Achievement Award from the American Society for Aesthetic Plastic Surgery. She was also named the 2011 National Newsmaker of the Year by the Community Anti-Drug Coalitions of America. She's also been awarded the Arthritis Foundation's Northeast Region Prize for Online Journalism, the Excellence in Women's Health Research Journalism Award, the Gold Award for Best Service Journalism from the Magazine Association of the Southeast, a Bronze Award from The American Society of Healthcare Publication Editors, and an honorable mention in the International Osteoporosis Foundation Journalism Awards. She was part of the writing team awarded a 2008 Sigma Delta Chi award for her part in a WebMD series on autism. Mann has a graduate degree from the Medill School of Journalism at Northwestern University in Evanston, Ill.