What Is Treatment-Resistant Depression?

Antidepressants don't always work

In This Article

Depression is usually reduced with medication, therapy, or a combination of the two. Usually, symptoms resolve with treatment. But sometimes, symptoms don’t get better with treatment.


Although definitions may vary, when two or more medications fail to provide expected relief, the illness may be considered “treatment-resistant depression.”

Treatment-resistant depression can be complex. Depression symptoms, such as sleep issues and appetite problems, may continue despite patient compliance with treatment. At other times, the symptoms resolve briefly but come back.

Just because depression doesn’t respond to the first couple of attempts at treatment, however, doesn’t mean it can’t be treated. It may require a different approach to treatment, however.


It’s estimated that between 30 and 60 percent of individuals with clinical depression may experience treatment-resistant depression.

Consequences for individuals with treatment-resistant depression can be significant. It’s associated with poor social function, medical comorbidity, and increased mortality.

Untreated depression is also a common cause of disability, so it’s important to continue trying to find strategies that can bring relief.

Individuals with untreated depression have a lifetime suicide risk of 2 to 15 percent.


It is important to note that estimates vary. However, it has been approximated that 30 to 50 percent of patients with depression may not respond to a particular antidepressant medication. But, before a physician or psychiatrist will consider a medication a treatment failure, they will consider the following questions:

  • How long was the medication administered? Most antidepressants take four to six weeks to reach their full effect. Before declaring a treatment is not working, providers will want to ensure that the medication has been taken long enough to be effective.
  • How closely did the patient adhere to the prescription? A prescription is usually only considered to be “adhered to” if it is taken according to the prescription at least 80 percent of the time. A few missed doses could greatly impact the ability of a medication to be effective. So before determining if a medication is a failure, a doctor will want to know if a patient has been compliant. Sometimes, doctors do pill counts or take other steps to monitor a patient’s medication.
  • Is the medication at a therapeutic dose? Sometimes medications are started at a low dose to minimize risk or side effects. As it’s tolerated, the dosage may be increased slowly. A physician will want to ensure the dosage is at a therapeutic level before determining whether the treatment is a failure.

    If a psychiatrist determines that the medication is a failure, there are some other treatment options that affect brain chemistry in a different way. Those options include:

    • Prescribing a different antidepressant. Just because one antidepressant doesn’t work doesn’t mean there aren’t any medication options. Sometimes physicians switch a patient to a different medication within the same class such as from Prozac to Zoloft, or from one class to a different one—for example, from Celexa to Wellbutrin to see if a different medication reaches the desired effect.
    • Changing to another type of antidepressant. Sometimes it’s helpful to switch from one class of antidepressant to another. Changing from a selective serotonin reuptake inhibitor (SSRI) to a Monoamine Oxidase Inhibitor (MAOI) for example, may be helpful because they affect chemicals in the brain differently.
    • Adding an additional type of medication. If antidepressants aren’t working, a prescriber may add a different type of medication (known as augmentation). Some antipsychotics, anticonvulsants, or antianxiety drugs, for example, may be used in conjunction with an antidepressant. Abilify, Seroquel, and Zyprexa are just a few examples of medications that may be used in conjunction with an antidepressant.

      Talk Therapy

      If a patient isn’t already attending therapy, a referral may be made. While there are many different types of psychotherapy that have been found to be beneficial in depression, cognitive behavioral therapy (CBT) has been found to be especially effective for treatment-resistant depression.

      Patients attending CBT may learn a variety of skills to manage their symptoms and improve their functioning.

      The goal of CBT may involve reframing negative thoughts, problem-solving, increasing social interaction, and increasing activity level. CBT may also help reduce sleep problems.

      Additional Treatment Options

      When medication and therapy aren’t reducing depression, a doctor may decide to turn to other treatment options. Here are some additional procedures that may be effective for treatment resistant depression:

      • Electroconvulsive therapy (ECT)Perhaps the most effective treatment for resistant depression is ECT. ECT is a procedure that is usually administered under general anesthesia. Electric currents are passed through the brain triggering a brief seizure. It seems to cause changes in brain chemistry that can reduce depression (and reverse symptoms of other mental illnesses). Although it is generally considered safe, it can have side effects such as some short-term memory loss and physical side effects. ECT is often initially administered two to three times per week for a total of six to 12 sessions.
      • Vagus nerve stimulation (VNS) — VNS is a surgical procedure that involves implanting a  pacemaker-like device in the body. It is attached to a stimulating wire that is threaded along the vagus nerve, which is thought to influence an area of the brain that regulates mood. Once implanted, the device delivers regular impulses to the brain via the vagus nerve. It can take several months for the effects to be felt.
      • Repetitive transcranial magnetic stimulation (rTMS) – rTMS involves using a magnet to stimulate certain areas of the brain. It has been used since 1985, and is being increasingly utilized, but there isn’t a lot of data available on the long-term success rate.
      • Ketamine – A type of anesthetic agent administered intravenously, ketamine has been found to be a potentially rapidly effective agent that can result in an improvement of depressive symptoms. Issues remain around how to sustain its effect long term.
      • Spravato (esketamine) nasal spray — The newest FDA approved option for treatment-resistant depression is a fast-acting nasal spray called esketamine. It is one of the two molecules that make up ketamine. Like ketamine, it needs to be administered under close observation of a doctor. 

      A Word From Verywell

      If you or a loved one is experiencing depression and medication isn’t working don’t give up. Talk to your physician or psychiatrist about other treatment options. It may take several attempts to find something that works well for you, but it’s important to keep trying so that you can experience relief from your symptoms.

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