Treatment-resistant depression: treatment options, definition, perspectives

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

This means they did not experience adequate symptom relief 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 is to switch from a first-line drug to an older antidepressant.

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

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

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 suffer from treatment-resistant depression.

MDD, also called clinical depression, can cause:

  • feelings of worthlessness and hopelessness
  • lack of energy and motivation
  • irritability and confusion
  • lack of sleep, appetite and libido

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

Augmentation therapy

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

Current first-line drugs include selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa), and serotonin-norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine (Pristiq) .

The main augmentation drugs include:

  • Lithium (Priadel). It 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) can have activity in 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 that 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.

Combine, optimize and change class

A doctor may recommend changing drugs, adjusting the dosage, or switching to another class of drugs.

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

A healthcare professional may also add another medication 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 behavior (CBT), which identifies and changes 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 medications or psychosocial interventions are not effective, a doctor may prescribe brain stimulation.

There are several types of brain stimulation. However, electroconvulsive therapy is 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 to 18 sessions.

New drugs

Some new drugs may relieve symptoms for some people with MDD.

In 2019, the Food and Drug Administration (FDA) approved esketamine (Spravato) for treatment-resistant depression. Doctors dispense this nasal spray to people 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.

New treatments

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

Another new treatment involves anti-inflammatory drugs.

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

Older research since 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 soon their symptoms may not to improve.
  • Drugs interactions. Some medications interact negatively or dangerously with antidepressants.
  • Skipping doses. A person must take antidepressants as directed for them to work properly. For most medications, this means taking the medication daily.
  • Genetic disorder. There is a genetic disease that prevents the synthesis of a substance that the body needs to make serotonin.
  • Disorders related to alcohol or drug abuse. These conditions can inhibit the treatment of depression.
  • Co-occurring medical or psychiatric conditions. These conditions require treatment at the same time a person is receiving treatment for depression.
  • Wrong diagnosis. It is possible that someone has an illness other than treatment-resistant depression.
  • Poor compliance. Environmental factors, such as a busy schedule or financial difficulties, can affect adherence to treatment.

Older searches states that unlike normal depression – which responds to typical treatment interventions – treatment-resistant depression manifests as:

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

According 2012 research, more than a third of people with treatment-resistant depression go into remission. The others have residual symptoms.

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

One of them is an old clinical trial 2004 who studied the effect of electroconvulsive therapy in 253 people with MDD. Results indicated that it produced remission in 75% of participants.

According to a study 2020, experts do not fully understand how remission works. They still have a lot to learn to help people achieve and maintain remission.

A diagnosis of treatment-resistant depression means a person has tried two different antidepressants that did not reduce symptoms enough. About a third of people with MDD suffer from treatment-resistant depression.

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

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