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

There are a variety of options used to manage treatment-resistant depression. A 2020 study discusses some of these methods, including adding drugs to a medication regimen, trying new drugs, psychotherapy, and more.

Augmentation therapy

This involves adding a second medication to a first-line antidepressant. The additional medication is usually not an antidepressant.

Current first-line medications include selective serotonin reuptake inhibitors (SSRI), such as citalopram (Celexa), and serotonin-norepinephrine reuptake inhibitors (SNRI), such as desvenlafaxine (Pristiq).

The main augmentation medications include:

  • Lithium (Priadel). This is a mood-stabilizing drug that doctors also use to treat bipolar disorder.
  • Thyroid hormone. Thyroid levels can affect mood, and the thyroid hormone triiodothyronine (T3) may have activity within the brain and spinal cord. Doctors can prescribe the synthetic form of T3, liothyronine (Cytomel).
  • Second-generation antipsychotics. These drugs treat conditions such as schizophrenia and borderline personality disorder (BPD). An example of an antipsychotic doctors use in augmentation therapy is quetiapine (Seroquel).
  • Bupropion (Wellbutrin). This antidepressant does not act on serotonin receptors, so it can be safely added to SSRIs or SNRIs.

Combining, optimizing, and changing classes

A doctor may recommend changing medications, adjusting the dosage, or switching to a different class of drug.

For example, if an SSRI or an SSNI is not effective, a doctor may prescribe an older class of drug, such as tricyclic antidepressants. An example of this type of drug is imipramine (Tofranil).

A healthcare professional may also add another drug to a person’s medication regimen or increase their dosage.


Doctors may use psychotherapy alone or in combination with other drug or non-drug therapies.

Examples of psychotherapy include cognitive behavioral therapy (CBT), which is identifying and changing unhealthy thought patterns, and interpersonal therapy, which focuses on improving interpersonal skills. These types of therapy can be valuable additions to a person’s treatment plan.

Brain stimulation

If medication or psychosocial interventions are not effective, a doctor may prescribe brain stimulation.

There are several types of brain stimulation. However, electroconvulsive therapy is the most effective. It involves the delivery of high-frequency electrical impulses to parts of the brain.

Usually, they will recommend two to three sessions per week for a total of 6–18 sessions.

New medications

Some new medications may provide symptom relief for some people with MDD.

In 2019, the Food and Drug Administration (FDA) approved esketamine (Spravato) for treatment-resistant depression. Doctors deliver this nasal spray to individuals in an office or clinic, and it quickly reduces symptoms in about half of people.

However, esketamine has significant side effects, including high blood pressure and dissociative symptoms.

Novel treatments

Some people have success with psilocybin, the psychedelic in hallucinogen mushrooms. Its mechanism of action may be somewhat similar to first-line traditional medications, such as SSRIs, which increase levels of serotonin in the brain.

Another novel treatment involves anti-inflammatory drugs.

Researchers believe inflammation plays a role in treatment-resistant depression, so they may use anti-inflammatory drugs to treat it. Medications in this category may include cyclooxygenase-2 inhibitors (COX-2 inhibitors) such as celecoxib (Celebrex) and infliximab (Remicade).

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 it’s safe to do so.

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.

Find 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.