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Treatment-Resistant Depression

Treatment-resistant depression is a type of depression that has not responded to at least 2 different treatments. About 33 percent of people with depression have treatment-resistant depression. In some cases, depression that was responding to treatment can become treatment-resistant over time.1

Symptoms of treatment-resistant depression

Treatment-resistant depression has the same symptoms as treatment-responsive depression. The most common symptoms of depression include:2-5

  • Depressed or sad mood
  • Loss of interest or pleasure in things you once enjoyed (anhedonia)
  • Weight changes
  • Sleep issues
  • Movement changes
  • Extreme tiredness (fatigue)
  • Feeling worthless or guilty
  • Trouble thinking or concentrating
  • Thinking about death or dying

Causes of treatment-resistant depression

We do not know why some people with depression do not respond to treatment. But there are some studies that suggest that experiencing high stress and trauma during childhood is linked to treatment-resistant depression.2,3

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Current high-stress life events can also lead to treatment-resistant depression. Plus, drinking alcohol or using recreational drugs can make depression treatment unsuccessful.2,3

Treatments for treatment-resistant depression

Drugs called selective serotonin reuptake inhibitors (SSRIs) are commonly used as the first treatment for depression. These drugs increase the amount of certain chemicals in the brain.1,3,6,7

It can take 6 to 8 weeks to see any changes in depression symptoms after starting to take these drugs. If your symptoms do not improve after trying 2 different antidepressants for a long enough time, then you might have treatment-resistant depression.1,3,6,7

Your doctor may suggest giving your current medication more time or increasing the dosage. There are also other treatment strategies for dealing with treatment-resistant depression:1,3,6,7


This approach includes adding a second drug to your treatment plan. This second drug is usually not used to treat depression on its own. Lithium is an example of a drug used as augmentation. One study reported that 60 percent of people who were given lithium as a second drug responded to the treatment.1

Trying different medicines

There are options when it comes to antidepressants. Different antidepressants work in different ways. They can affect different chemicals in the brain. About 60 percent of the people need to try a few different antidepressants until they find one that works for them.3,6


Talking to a therapist can be very beneficial along with taking prescription drugs for depression. For a lot of people, therapy combined with the right prescription drugs works best. Therapy can provide ways to deal with situations or life events that might be the cause of depression. Therapy can also help identify and reduce negative patterns and behaviors.6

Brain stimulation

There are other treatments for depression that do not involve drugs. These treatments include stimulating or activating different parts of the brain. For example, electroconvulsive therapy (ECT) sends electrical current through the brain. This causes an increase in electrical activity in the brain. ECT can be a successful treatment for depression, but it is not commonly used. Usually, these treatments are only used after trying different drugs and therapy.1


Ketamine is a drug that is used for severe depression. Unlike other antidepressants, ketamine can reduce the symptoms of depression within hours. Ketamine can only be given in a clinic under a doctor's supervision. In 2019, the US Food and Drug Administration approved esketamine, which is a version of ketamine that is given through the nose.1,3,7

Not everyone’s depression is the same. There are hundreds of different combinations of symptoms that can get diagnosed as depression. This diversity of symptoms means that the underlying cause of depression may also be different for each person. This can explain why some people need to try many different treatments for depression before finding one that works for them.2

If your first treatment for depression does not work, know that there are other options available. Meet with your doctor regularly to discuss how you are feeling and how your treatment is working for you.