An Overview of Treatment-Resistant Depression

Antidepressants don't always work

Verywell / Bailey Mariner 

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

Although definitions may vary, when two or more treatment attempts of adequate dose and duration fail to provide expected relief, the disorder 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.

It's important to remember that even if depression does not respond to the first couple of treatments, that doesn't mean it cannot be treated. But it may require a different approach to treatment. You should work with your doctor to monitor your symptoms and response to treatment so that you can find an option that works for you.


Studies have found that 30% to 40% of people only experience a partial remission of depressive symptoms after taking antidepressants. Approximately 10% to 15% of people don't respond to antidepressant treatments at all.

Consequences for people with treatment-resistant depression can be significant. It’s associated with poor social functioning, 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.

People with untreated depression have a lifetime suicide risk of 2% to 15%.


Treatment-resistant depression can manifest as:

  • A lack of any response to medication or psychotherapy treatment
  • Not enough of a response to standard depression treatments
  • Brief improvements followed by a return of depressive symptoms

Because standard treatments do not work well or at all, people may begin to experience profound hopelessness. Symptoms can drag on for months without feeling any relief or improvement in mood. 


Doctors and researchers are not entirely sure what causes treatment-resistant depression. Some theories include:

  • Genetics: Researchers believe that inherited characteristics may play a role in how people's bodies respond to different antidepressants. While some genes have been associated with treatment-resistant depression, further research is needed to identify genetic biomarkers. 
  • Misdiagnosis: Poor response to standard depression treatments can also occur when people have been incorrectly diagnosed with depression. While they may have symptoms of major depressive disorder, they may actually have a different condition such as bipolar disorder.
  • Metabolic abnormalities: Some research has suggested that metabolic disorders and nutritional deficiencies can play a role in treatment-resistant depression. One study found, for example, that folate (vitamin B9) deficiency was more common in people with depression resistant to treatment. Further research in this area is needed to determine the exact impact of metabolic conditions.


If you have been treated for depression but your symptoms have not improved, you should talk to your doctor. Treatment-resistant depression is not an official diagnosis included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), nor is it consistently defined. Some experts suggest that it is defined as having had two different antidepressant trials without relief, while others suggest that it can take as many as four different treatments before depression should be identified as resistant.

In any case, you should always talk to your doctor about your symptoms and concerns. If you have not experienced any relief, only minimal relief, or a complete return of symptoms, you may need a different type of antidepressant or other approaches to your treatment.

Your doctor may:

  • Review the treatments that you have tried so far
  • Consider the type of response you have shown to treatments
  • Assess your current physical health and consider underlying medical conditions
  • Consider a diagnosis of other psychiatric disorders
  • Evaluate other medications and supplements you are currently taking

If your doctor believes that you have treatment-resistant depression, they may recommend a different dosage, medication, or treatment approach. Your doctor may also refer you to a psychiatric consultant for additional treatment advice and options.


While estimates vary, it is believed that anywhere 30% to 50% of patients with depression may not respond to a particular antidepressant medication. 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 a significant percentage of the time. 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 adherent. 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 your current 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 in the same class: 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 (fluoxetine) to Zoloft (sertraline) to see if a different medication has 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) or Wellbutrin (bupropion), for example, may be helpful because they affect brain chemistry somewhat differently.
  • Adding an additional type of medication: If antidepressants aren’t working, your doctor may add a second medication (known as augmentation). Some anticonvulsants or antianxiety drugs, for example, may be used in conjunction with an antidepressant. Some doctors may prescribe antipsychotic medications. However, research suggests that mixing an antidepressant with an atypical antipsychotic, such as Abilify (aripiprazole), Seroquel (quetiapine), and Zyprexa (olanzapine), is associated with an increased risk of death.

Talk Therapy

If you aren't already attending psychotherapy, a referral may be made to a mental health professional who offers it.

While there are many different types of psychotherapy that have been found to be beneficial in depression, cognitive behavioral therapy (CBT) has data that found it effective for treatment-resistant depression.

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

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

Some other types of therapy that may also be helpful include interpersonal therapy, dialectical behavioral therapy, and psychodynamic therapy in both individual and group settings.

Other Treatment Options

When medication and therapy aren’t reducing depression, your 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 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 as well as some physical side effects. ECT is often initially administered two to three times per week. The duration of the treatment can vary but a total of six to 12 sessions is common.
  • 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 in treatment-resistant depression.
  • 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. 


Dealing with treatment-resistant depression can be difficult for a number of reasons. Not only are you coping with persistent symptoms of depression, but you are also struggling with the difficulty in treating your condition.

Some of the things you can do that can help:

  • Follow your treatment plan. Even if it feels like you aren't experiencing improvements, it's important to take your medication as prescribed and attend recommended therapy sessions. Both therapy and antidepressants take time to work.
  • Find ways to manage your stress. Unhappiness and stress that stems from areas of your life such as relationships, work, school, and finances can also contribute to feelings of depression. Stress management techniques such as meditation, journaling, progressive muscle relaxation, and yoga may provide some benefits and relief.
  • Avoid drugs and alcohol. Substance use can not only worsen symptoms of depression; it can also cause interactions with your antidepressant medications. Always talk to your doctor about any substances, other medications, or even natural supplements that you are taking.
  • Practice good self-care. While it can be difficult to do when you are feeling depressed, caring for yourself by eating healthy, sleeping enough, and exercising regularly may help you better manage your symptoms.

If you are having suicidal thoughts, contact the National Suicide Prevention Lifeline at 988 for support and assistance from a trained counselor. If you or a loved one are in immediate danger, call 911.

For more mental health resources, see our National Helpline Database.

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.

4 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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  2. Fabbri C, Corponi F, Souery D, et al. The genetics of treatment-resistant depression: A critical review and future perspectives. Int J Neuropsychopharmacol. 2019;22(2):93-104. doi:10.1093/ijnp/pyy024

  3. Pan LA, Martin P, Zimmer T, et al. Neurometabolic disorders: Potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. Am J Psychiatry. 2017;174(1):42-50. doi:10.1176/appi.ajp.2016.15111500

  4. Gerhard T, Stroup TS, Correll CU, et al. Mortality risk of antipsychotic augmentation for adult depression. PLoS One. 2020;15(9):e0239206. doi:10.1371/journal.pone.0239206

Additional Reading

By Amy Morin, LCSW, Editor-in-Chief
Amy Morin, LCSW, is the Editor-in-Chief of Verywell Mind. She's also a licensed clinical social worker, psychotherapist, and international bestselling author. Her books, including "13 Things Mentally Strong People Don't Do," have been translated into more than 40 languages. Her TEDx talk,  "The Secret of Becoming Mentally Strong," is one of the most viewed talks of all time.