Treatment-Resistant Depression

Medically Reviewed by Smitha Bhandari, MD on January 27, 2023
11 min read

How well is your depression treatment working? Does it help a bit, but you still don't feel as if the darkness has lifted? Perhaps you feel the treatment isn't working at all. If so, you could have treatment-resistant depression (TRD), also called refractory depression.

Unfortunately, depression treatments don't always work. As many as two-thirds of people with depression aren't helped by the first antidepressant they try. Up to a third don't respond to several attempts at treatment.

But if your depression treatment isn't working, don't give up. Most people can get their treatment-resistant depression under control. You and your doctor just need to find the right approach. This might include different drugs, therapy, and other treatments. If you're still struggling with depression despite treatment, here's what you need to know.

What is treatment-resistant depression? Surprisingly, that can be hard to answer. Experts still disagree on what exactly the term means.

Some researchers define it as a case of depression that doesn't respond to two different antidepressants from different classes. Other experts say that a person needs to try at least four different treatments before depression can be truly considered treatment-resistant.

Of course for you, the exact definition doesn't matter. You just need to ask yourself some basic questions.

  • Has your treatment failed to make you feel better?
  • Has your treatment helped a bit, but you still don’t feel like your old self?
  • Have the side effects of your medication been hard to handle?

If the answer is yes to any of these, you need to see your doctor. Whether or not you actually have treatment-resistant depression, you need expert help.

Some other signs include:

  • More frequent, severe, and longer episodes of depression
  • Short moments of improvement followed by depression symptoms
  • More anxiety or an anxiety disorder

 You may be more likely to develop it because of a few things. Risk factors for this condition include if:

  • The onset of your depression began at an earlier age
  • You have more frequent and recurring depression episodes
  • Your depression episodes last longer
  • You have a severe case of depression
  • You’re older in age

A primary care doctor can treat depression. Research suggests that primary care doctors prescribe 60%-65% of antidepressantsBut it may be best to see a specialist, like a psychiatrist, if you think you may have treatment-resistant depression. It's also a good idea to also work with a therapist, like a psychologist or social worker. This is because the best treatment is often a combination of medicine and therapy.

Treatment-resistant depression can be hard to diagnose. Sometimes, other conditions or problems can cause similar symptoms. So when you meet with your doctor, they will want to:

Confirm your diagnosis. Some people who seem to have treatment-resistant depression have a diagnosis of unipolar depression alone. But this may not be accurate. If you have bipolar disorder, antidepressants may be less effective than in unipolar depression. And medical conditions such as hypothyroidism can cause symptoms of depression. When your diagnosis isn’t accurate, it’s harder to get the right treatment.

When major depressive disorder is accompanied by other medical or psychiatric disorders such as anxiety or eating disorders, depression often is harder to treat. This is especially true if these other disorders don't receive their own independent treatment.

Make sure you've been using your medicine correctly. Up to half of people who get prescription drugs for depression don't take them as recommended. They miss doses or stop taking them because of side effects. Some give up too soon. It can take 4-12 weeks for a medicine to take effect. Sometimes they take their medicine at too low a dose, so it doesn’t work as well as it should.

Check for other causes. Other issues, ranging from thyroid problems to using drugs or alcohol, can worsen or cause depression. So can many medicines used to treat common medical problems. Sometimes, switching medicines or treating an underlying condition can resolve a hard-to-treat depression.

You may wonder why some people do so well with the first medication they try, while you don’t. Experts don't know for sure, but we do know that not all depressions are the same for everyone. Evidence also suggests that those with especially severe depression or long-term depression may find it harder to find the right treatment.

Different antidepressants work in different ways to affect specific chemicals (neurotransmitters) that send information along brain circuits that regulate mood. If your current medicine isn't helping -- or isn't helping enough -- other drugs might. There are two basic approaches:

Switching medicines. There are a number of different classes of antidepressants, including SSRIs, such as:

  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluoxetine (Prozac)
  • Paroxetine (Paxil)
  • Sertraline (Zoloft)

And SNRIs, including:

  • Desvenlafaxine (Khedezla, Pristiq)
  • Duloxetine (Cymbalta)
  • Levomilnacipran (Fetzima)
  • Venlafaxine (Effexor)

Newer antidepressant medicines that affect many different serotonin receptors in the brain include vilazodone (Viibryd) and vortioxetine (Trintellix, formerly called Brintellix).

Older classes of antidepressants include tricyclics like:

  • Amitriptyline (Elavil)
  • Doxepin (Adapin)
  • Imipramine (Tofranil)
  • Nortriptyline (Aventyl, Pamelor)

And tetracyclics such as: 

  • Amoxapine (Asendin)
  • Maprotiline (Ludiomil)
  • Mazindol (Mazanor)
  • Mirtazapine (Remeron)

Some antidepressants, such as bupropion (Wellbutrin) or mirtazapine (Remeron), are thought to affect the brain chemicals dopamine and norepinephrine through unique mechanisms. They’re often combined with other antidepressants in order to take advantage of their combined effects.

Another older class of antidepressants called MAO inhibitors affect a special enzyme inside brain cells that can increase the functioning of several different neurotransmitters. These include:

  • Isocarboxazid (Marplan)
  • Phenelzine (Nardil)
  • Selegiline (Emsam)
  • Tranylcypromine (Parnate)

Your doctor will consider how the possible side effects might affect you specifically to get a good match. For instance, some antidepressants can increase the risk of weight gain. For some, that might be unacceptable or even dangerous. But for others -- like people who have lost weight during a depression -- it could actually be a good idea.

Of course, one of the things your doctor might need to do is get you off some of the medications you're on now. If you've been struggling with treatment-resistant depression for a long time, you might have accumulated a lot of different prescriptions over the years. Some of those drugs might not have any purpose. Others might be interacting with each other, or even worsening your symptoms.

When you're trying a new drug for treatment-resistant depression, make sure to give it a fair chance. Cook says that many people who think they are treatment-resistant -- because they've tried a number of antidepressants without success -- might not be. Instead, they just weren't on the medicine long enough to know one way or another. Side effects are often the reason.

Different antidepressants work in different ways to affect specific chemicals (neurotransmitters) that send information along brain circuits that regulate mood. If your current medicine isn't helping -- or isn't helping enough -- other drugs might. There are two basic approaches:

  1. Switching medicines. There are a number of different classes of antidepressants, including SSRIs. Another option is to switch from one drug to another in the same class. A person who wasn't helped by one SSRI could still benefit from a different one.
  2. Adding a medicine. In other cases, your doctor might try adding a new medicine to the antidepressant you're already using. This is called adjunct therapy. This can be especially helpful if your current drug is partly helping but not completely relieving your symptoms.

One option is to add a second antidepressant from a different class, called combination therapy. Another approach, called augmentation therapy, adds a medicine not typically used to treat depression, like an antipsychotic, or an anticonvulsant such as lithium.

Aripiprazole (Abilify), brexpiprazole (Rexulti), or quetiapine (Seroquel XR) are FDA-approved as add-on therapies to an antidepressant for treatment-resistant depression.

Olanzapine/fluoxetine (Symbyax) is a combination drug that contains the active ingredients in fluoxetine (Prozac) and olanzapine (Zyprexa) together in one tablet and is approved for the acute treatment of treatment-resistant depression. 

Esketamine nasal spray (Spravato) may be used along with an oral antidepressant for the treatment of depression in adults who’ve tried other antidepressant medicines but haven’t benefited from them. Esketamine isn’t a narcotic. It’s a strong variant of the drug ketamine.

One drawback to this approach is that the more medicines you take, the greater potential for side effects or drug interactions.

People have different reactions to the drugs used for treatment-resistant depression. What works best for one person might have no benefit for you. And unfortunately, it's hard for your doctor to know beforehand what drug or combination of drugs will work best. Arriving at the right treatment can take patience.

Your doctor may instead decide that you don’t need a new depression medication. They might have you adjust your current drug’s dosage. Or they may have you take another medication that isn’t typically for depression.

For example, your doctor may prescribe ketamine alongside your other depression drugs. This medication works quickly to combat symptoms of depression.

Ketamine can affect your mood, thought process, and patterns and may lower the inflammation that’s related to mood disorders. The drug manages depression in a different way than other depression treatments do. Because of this, it might be a good option if you have treatment-resistant depression.

Drugs aren't the only approach to treating treatment-resistant depression. Some other methods are:

Talk therapy. Approaches like cognitive behavioral therapy, which focuses on concrete goals and how your own thoughts and behaviors contribute to your depression, can help people with depression. There’s some evidence it works especially well with treatment-resistant depression.

If you've tried therapy in the past and it hasn't helped, you could try again. Think about seeing a new therapist. Or look into a different therapeutic approach. For instance, if one-on-one therapy didn't do much for you, ask your doctor if group therapy or a different approach might be worth a try.

Acceptance and commitment therapy. This is a form of cognitive behavioral therapy that helps you adopt positive behaviors when harmful thoughts and emotions cloud your mind. Doctors use this form of therapy specifically for people who are treatment-resistant.

Therapy for your relationships. You may want to try interpersonal psychotherapy (which focuses on issues in your relationship and how they may tie to depression) or family and marital therapy (which can help ease stress and address some of your depression symptoms).

Dialectical behavioral therapy. If you have ongoing thoughts of suicide or self-harm (things that may be common in TRD), this form of therapy can help you learn acceptance and problem-solving skills.

Mindfulness. This technique helps you accept your thoughts without labels. You’ll receive emotions as they are and avoid judging them as “good” or “bad.”

Behavioral activation. With this method, you’ll slowly become more engaged in activities that you used to love or new ones that may boost your overall mood. This will help you feel less isolated.

Electroconvulsive therapy (ECT). ECT is typically used in people with serious or life-threatening depression that can’t be resolved by other treatments, or in significant depressive episodes that have not gotten better after several medication trials. It uses electric impulses to trigger controlled seizures in the brain. A series of ECT treatments (usually 6-12 over a few weeks) can often rapidly relieve depression. But some form of continued therapy (either a medicine or else periodic ECT "booster" treatments) is usually necessary to prevent relapse.

VNS (vagus nerve stimulation). This approach is also used in people with serious depression that hasn't responded to other treatments. Like ECT, it uses electrical stimulation to relieve the symptoms of depression. The difference is that the device is surgically implanted in your body. VNS is FDA-approved for the long-term treatment of chronic depression that doesn’t respond to at least two antidepressants. Its effects may take up to 9 months to appear, and studies have shown that a meaningful response seems to occur only in about 1 in 3 people.

Transcranial magnetic stimulation (TMS). This is a noninvasive approach. Like ECT and VNS, it uses electrical stimulation to treat depression. Unlike those procedures, TMS poses few side effects. It may be best for seriously depressed people who are mildly resistant to drug therapy. You’ll have treatment on an outpatient basis 4 to 5 days a week for 4 or more weeks. It’s considered safe but appears not to be as effective as ECT.

Experimental techniques. Experts are researching new techniques to tackle treatment-resistant depression, like deep brain stimulation and MST (magnetic seizure therapy.) Although some studies have been promising, more research needs to be done. But if you're interested in trying them, talk to your doctor about joining a clinical trial.

Sometimes, a doctor might recommend hospitalization for treatment-resistant depression. It could be the best option if your depression is severe and you're at risk of hurting yourself. A stay in the hospital also offers a way for you to recover from your depression in a safe and stable environment. You’ll get a break from some of the daily stresses that might contribute to your condition. Your doctors will also get a chance to work together on a good treatment plan.

Arriving at the right treatment can take some trial and error. But whatever you do, don't settle. Don't give up and accept the symptoms of depression. You just need to find the right one for you.

In the meantime, adopt some of these tips to help live with the symptoms of depression:

  • Stick with your treatment plan and therapy sessions until your doctor tells you otherwise.
  • Don’t drink or misuse drugs.
  • Get enough sleep.
  • Manage your stress levels.
  • Make time to exercise.

It’s important to work with the right expert as you search for the best treatment option. You’ll want to look into a psychiatrist that specializes in treatment-resistant depression. To find one, you can ask your current doctor for recommendations.

There are a few programs that also offer specific care for treatment-resistant depression. You can research options in your area or ask your medical team to help find one. You might consider specialized programs like Emory Healthcare’s Treatment Resistant Depression Program.

Programs like this are preferable because they focus on your specific needs with treatment-resistant depression. Other depression experts may give good insight, but they won’t be able to address your condition as deeply as a specialist would.

Psychiatrists that specialize in treatment-resistant depression will carefully review your medical history, treatments, and other medical conditions. They’ll use this to decide on a proper treatment plan for you.