Standard treatments relieve depression for many people, but they don’t work for everyone. At least 30% of those who try two or more antidepressants continue to have severe symptoms. This is called treatment-resistant depression.

If it happens to you, know that there are still ways to manage your depression. Talk to your doctor about all your treatment options.

“The most important point is not to give up,” says Dr. John Krystal, chair of the Department of Psychiatry at Yale School of Medicine and a pioneer in research on ketamine and depression. “There are many of these options, current and emerging, that can really make a difference in a person’s life.”

What is treatment-resistant depression?

Experts do not agree on a definition. But in general, it is a form of depression that does not improve after trying two antidepressants from different classes of medications. “If you have to turn to a third medication, that’s the standard threshold,” Krystal says.

For example, he says your doctor might diagnose you with treatment-resistant depression after you are first treated with a selective serotonin reuptake inhibitor (SSRI), such as fluoxetine, and you don’t respond. And then they treat him with a serotonin and norepinephrine reuptake inhibitor (SNRI), like venlafaxine or duloxetine, and he doesn’t respond to that either.

“Medication acts as a kind of filter,” says Krystal. “If you respond to that, then by definition you don’t have treatment-resistant depression.”

How to get a diagnosis

Before receiving a diagnosis of treatment-resistant depression, Krystal says she will have to go through two rounds of antidepressant treatments. Typically, that means giving each antidepressant 6 to 8 weeks to take effect. And if her first dose of antidepressants doesn’t help, her doctor might increase the amount of medication she takes before switching to another medication.

Crystal Clark, MD, associate professor of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine, says it’s important to maximize the dosage of each antidepressant.

“Sometimes we will see that people have tried several [antidepressants] That hasn’t worked, but they’ve only tested half the potential dose. “It may not necessarily be a failed trial.”

Your doctor may also look for hidden causes that could explain why your drug treatments are not working. There are a “set of different reasons” why people don’t respond to antidepressants, Krystal says, including things like:

• You don’t take your medication every day.
• Your body does not absorb the drug.
• You have another health condition, such as an underactive thyroid.

External issues can also play a role. “Some people don’t respond [to antidepressants] because they have so much going on in their lives and they experience such stress and confusion that the resolution of their depression is masked or prevented,” Krystal says.

What causes treatment-resistant depression?

There are some theories about genetic and brain differences, Clark says, but there is no biomarker or other mechanism that can identify people who will have treatment-resistant depression. “There is no definitive answer to that question.”

Krystal says there are “many different groups of people” who don’t respond to antidepressants. Researchers are trying to figure out the biology behind this. This could lead to more personalized treatment in the future. “That strategy is called precision medicine,” she says.

Experts are specifically investigating how this targeted approach could help certain groups, such as those who have treatment-resistant depression and high inflammation. Krystal says this includes people with conditions such as arthritis, asthma, heart disease, inflammatory bowel diseases, and who are overweight or obese.

In general, the chances of suffering from depression increase when inflammation continues. And Krystal says there’s some evidence that the amount of inflammation you have can predict whether you’ll respond to antidepressants. She says there is promising evidence that immunosuppressive medications, which block proinflammatory cytokine signals, could help relieve symptoms for certain people with treatment-resistant depression.

Symptoms

There is no specific set of symptoms that differentiates treatment-resistant depression from other forms of depression. Experts agree that it would be much easier if that were the case. But Krystal says her antidepressant definitely doesn’t work if she wakes up every morning and thinks, “I don’t know how I’m going to get through the day.”

Krystal says that if you don’t have joy, pleasure, or excitement in your life, “it’s a good time to start talking to a therapist, counselor, or doctor about what’s going on.”

Here are some other questions to assess whether your antidepressant is helping:

• To what extent have you returned to your old self?
• Do you sleep too much or too little?
• Do some parts of your life not seem right to you?
• Has your appetite returned to normal?

How to manage treatment-resistant depression

Antidepressants alone may not work very well. Seek help from a doctor who will give you more options. “I encourage people to make sure they work with a psychiatrist who is comfortable running the gamut,” Clark says. “Not just oral therapies, but someone who has knowledge of some of the most advanced and novel treatments.”

Treatment options for treatment-resistant depression include:

Complementary medication. Your doctor may add other medications along with your antidepressant. Everyone is different, but common options may include antipsychotics, mood stabilizers, anti-anxiety medications, thyroid hormone, or other drugs. Your doctor may also suggest pharmacogenetic testing to look for specific genes that show how well you process certain antidepressants.

Talk therapy. There is evidence that psychotherapy can relieve depression in some people who do not respond well to antidepressant drugs. “However, often when we talk about treatment-resistant depression and think about interventions, we don’t always include cognitive behavioral therapy, family therapy, or supervised work therapy,” Krystal says. These therapies can help:

• Cognitive behavioral therapy: Focuses on thoughts, emotions, and behaviors that affect your mood. CBT can help you become aware of your negative thoughts and work to shift to a more positive mindset.
• Dialectical Behavior Therapy: Helps you develop your acceptance and problem-solving skills. This is especially helpful for people who self-harm or have repeated suicidal thoughts.
• Behavioral Activation: Slowly reduces avoidance and isolation and helps people engage in things they once enjoyed or activities that make them feel better.
• Group therapy: involves other people who have depression working together with a therapist.
• Family or couples therapy: Works to reduce stress in relationships with family members or your spouse or partner. In many cases, this can help with depression.

Ketamine. Your doctor may suggest this medication to give you quick relief from treatment-resistant depression. You will take it in low doses intravenously. The FDA has approved a form of nasal spray called esketamine (Spravato). Doctors often recommend that you take an oral antidepressant along with esketamine or ketamine.

Brain stimulation. Your doctor may want you to go this route if nothing else works or if your symptoms are really severe. These procedures include:

• Repetitive transcranial magnetic stimulation (rTMS): Magnetic fields are used to stimulate nerve cells in the area of ​​the brain that involves mood and depression.
• Electroconvulsive therapy (ECT): A small dose of electricity is passed through the brain while you sleep. That causes a brief seizure, which can change brain chemistry to help relieve symptoms of major depression. Some side effects, such as confusion or memory loss, may occur, but they usually do not last long.
• Vagus nerve stimulation (VNS): A device is implanted in the chest with a wire that goes to the vagus nerve in the neck. Electrical impulses travel from that nerve to the area of ​​the brain that controls moods. That can improve your depression. This procedure is usually tried only if ECT and rTMS do not work.

Tell your doctor if you don’t feel 100% better. The goal of your treatment should be the same as other health conditions, Krystal says, such as cancer, heart attacks, or broken bones. “In other words, we don’t go to an orthopedic surgeon and say, ‘I broke my leg, but I want it to be 60% better.’ We tell the orthopedic surgeon, ‘I want my leg fixed.'”