If a person with major depressive disorder (MDD) has not responded to at least two types of medication, they have treatment-resistant depression.

This means that they have not experienced adequate relief from their symptoms after trying two different treatment methods.

Although treatment-resistant depression can be difficult to manage, doctors have a variety of interventions to treat it. One choice involves changing from a first-line medication to an older antidepressant drug.

Alternatively, a healthcare professional may add a non-antidepressant drug to a person’s medication regimen. They may also recommend psychotherapy, brain stimulation, or new drugs.

Read more to learn about treatment-resistant depression, how doctors manage it, and more.

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Doctors classify cases of MDD as treatment-resistant depression when two antidepressants from two different drug classes do not relieve a person’s symptoms.

According to a 2021 study published in the Journal of Clinical Psychiatry, 30.9% of people in the United States who take medication for their MDD have treatment-resistant depression.

MDD, also called clinical depression, can cause:

  • feelings of worthlessness and hopelessness
  • low energy and motivation
  • irritability and confusion
  • poor sleep, appetite, and sex drive

Older research from 2012 notes that a combination of risk factors contribute to treatment-resistant depression, including:

  • Not staying on medication long enough. It can take 6–8 weeks for a drug to work properly, so if a person stops too early, their symptoms may not improve.
  • Drug interactions. Some medications interact adversely or dangerously with antidepressants.
  • Skipping doses. An person must take antidepressants according to the directions in order for them to work properly. For most medications, this means taking the drug daily.
  • Genetic disorder. There is a genetic condition that prevents the synthesis of a substance the body needs to make serotonin.
  • Alcohol or drug misuse disorders. These conditions can inhibit depression treatment.
  • Co-occurring medical or psychiatric conditions. These conditions need treatment at the same time that a person receives treatment for depression.
  • Wrong diagnosis. It is possible that someone has a condition other than treatment-resistant depression.
  • Poor compliance. Environmental factors, such as a busy schedule or financial challenges, can affect treatment compliance.

Older research indicates that unlike normal depression — which responds to typical treatment interventions — treatment-resistant depression manifests in:

  • poor quality of life
  • functional impairment
  • self-harming behavior
  • high relapse rate
  • suicidal ideation

Suicide prevention

If you know someone at immediate risk of self-harm, suicide, or hurting another person:

  • Ask the tough question: “Are you considering suicide?”
  • Listen to the person without judgment.
  • Call 911 or the local emergency number, or text TALK to 741741 to communicate with a trained crisis counselor.
  • Stay with the person until professional help arrives.
  • Try to remove any weapons, medications, or other potentially harmful objects.

If you or someone you know is having thoughts of suicide, a prevention hotline can help. The 988 Suicide and Crisis Lifeline is available 24 hours a day at 988. During a crisis, people who are hard of hearing can use their preferred relay service or dial 711 then 988.

Click here for more links and local resources.

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According to research from 2012, more than one-third of people with treatment-resistant depression go into remission. The remainder have residual symptoms.

However, a few studies suggest electroconvulsive therapy produces a higher rate of remission.

One of these is an older 2004 clinical trial that investigated the effect of electroconvulsive therapy in 253 people with MDD. The results indicated that it produced remission in 75% of the participants.

According to a 2020 study, experts do not fully understand how remission works. They still have much to learn about helping people reach and maintain remission.

A diagnosis of treatment-resistant depression means a person has tried two different antidepressants that did not provide sufficient symptom reduction. About one-third of people with MDD have treatment-resistant depression.

A doctor may recommend adding or changing medications, psychotherapy, electroconvulsive therapy, or new or novel medications.