Standard treatments relieve depression for many people, but don’t work for everyone. At least 30% of those who try two or more antidepressants continue to have severe symptoms. That’s called treatment-resistant depression.
If it happens to you, keep in mind that there are still ways to cope with your depression. Talk to your doctor about all your treatment choices.
“The key point is not to give up,” says John Krystal, MD, chairman of the Department of Psychiatry at the Yale School of Medicine and a pioneer in ketamine and depression research. “There are so many of these options – current and emerging – that can really make a difference in someone’s life.”
What is treatment-resistant depression?
Experts don’t agree on a single definition. But generally speaking, it’s a form of depression that doesn’t improve after trying two antidepressants from different classes of medications. “If you need to go to a third drug, that’s the standard threshold,” says Krystal.
For example, he says, your doctor may diagnose you with treatment-resistant depression after first treating you with a selective serotonin reuptake inhibitor (SSRI), such as fluoxetine, and you don’t respond. And then you are treated with a serotonin-norepinephrine reuptake inhibitor (SNRI), such as venlafaxine or duloxetine, and you do not respond to that either.
“Medicines act as a kind of filter,” says Krystal. “If you respond to it, by definition you don’t have treatment-resistant depression.”
How to get a diagnosis
Before you’re diagnosed with treatment-resistant depression, Krystal says you should take two rounds of antidepressants. This usually means that each antidepressant should work for six to eight weeks. And if the dose of your first antidepressant doesn’t help, your doctor may increase the amount of medicine you take before switching to another medicine.
Crystal Clark, MD, associate professor of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine, says it’s important to maximize the dose of any antidepressant.
‘Sometimes we see that people have tried several [antidepressants] that didn’t work, but they only tried half the potential dose. That doesn’t necessarily have to be a failed process.”
Your doctor may also look for hidden causes that may explain why your drug treatments aren’t working. There’s a “cluster of different reasons” why people don’t respond to antidepressants, says Krystal, including things like:
- You do not take your medications every day.
- Your body does not absorb the medicine.
- You have another health condition, such as an underactive thyroid gland.
External problems can also play a role. ‘Some people don’t respond [to antidepressants] because there is so much going on in their lives, and they are experiencing so much stress and anxiety, that the resolution of their depression is being masked or prevented,” says Krystal.
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 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 why this is so. This could eventually lead to more personalized treatment. “That strategy is called precision medicine,” he says.
Experts are specifically investigating how this targeted approach can help certain groups, such as people with treatment-resistant depression and high levels of inflammation. Krystal says this includes people with conditions such as arthritis, asthma, heart disease, inflammatory bowel disease and those who are overweight or obese.
In general, the risk of depression increases if you have persistent inflammation. And Krystal says there’s some evidence that the amount of inflammation you have can predict whether you’ll respond to antidepressants. He says there is promising evidence that immunosuppressive medications, which block signals from pro-inflammatory cytokines, may help alleviate symptoms in some people with treatment-resistant depression.
Symptoms
There is no specific set of symptoms that makes treatment-resistant depression different from other forms of depression. Experts agree that it would be a lot easier if that were the case. But Krystal says your antidepressant is definitely not working if you wake up every morning thinking, “I don’t know how I’m going to get through the day.”
Krystal says that if you’re not having joy, fun, or excitement in your life, “this is a good time to talk to a therapist, counselor, or doctor about what’s going on.”
Here are some other questions to gauge if your antidepressant is helping:
- To what extent are you back to your old self?
- Do you sleep too much or too little?
- Do certain parts of your life feel off?
- Is your appetite back to normal?
How to treat treatment-resistant depression
Antidepressants alone may not work as well. Seek help from a doctor who gives you more options. “I encourage people to make sure they work with a psychiatrist who is comfortable moving through the spectrum,” says Clark. “Not just with oral therapies, but someone who has knowledge of some of the more advanced and new treatments.”
Treatment options for treatment-resistant depression include:
Additional medication. Your doctor may add other medicines to match your antidepressant. Everyone is different, but common choices may include antipsychotics, mood stabilizers, anxiety medications, thyroid hormone, or other medications. Your doctor may also suggest pharmacogenetic testing to check for specific genes that show how well you process certain antidepressants.
Talk therapy. There is some evidence that psychotherapy can alleviate depression in some people who do not respond well to antidepressants. “But often when we talk about treatment-resistant depression and think about interventions, we don’t always mean cognitive behavioral therapy, family therapy, or supervised work therapy,” says Krystal. These therapies can help:
- Cognitive Behavioral Therapy: Focuses on thoughts, emotions, and behaviors that influence your mood. CBT can help you become aware of your negative thoughts and work towards a change to a more positive mindset.
- Dialectical behavior therapy: Helps you develop problem-solving and acceptance skills. This is especially helpful for people who self-harm or repeatedly have 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: where other people with depression work together with a therapist
- Family or marriage therapy: Works to reduce stress in your relationships with family members or your spouse or partner. In many cases this can help with your depression.
Ketamine. Your doctor may suggest this medication to give you quick relief from treatment-resistant depression. You take it in low doses through an IV. The FDA has approved a nasal spray form called esketamine (Spravato). Doctors typically 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 very severe. These procedures include:
- Repetitive transcranial magnetic stimulation (rTMS): Magnetic fields are used to stimulate nerve cells in the area of your brain where mood and depression play a role.
- Electroconvulsive therapy (ECT): A small dose of electricity is sent through your brain while you sleep. That causes a brief attack, which can change brain chemistry to relieve symptoms of major depression. Some side effects may occur, including confusion or memory loss, but these usually do not last long.
- Vagus nerve stimulation (VNS): A device is implanted in your chest with a wire that goes to the vagus nerve in your neck. Electrical impulses travel from that nerve to the part of your brain that controls mood. That can improve your depression. This procedure is usually only attempted 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 problems, 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 say to the orthopedic surgeon, “I want my leg repaired.” “