Managing Treatment-Resistant Depression

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Treatment-resistant depression (TRD) occurs when major depressive disorder (MDD) treatment does not work. There is no official definition or set criteria for TRD, but the measure often used is an inadequate response to at least two trials of antidepressant medications.

The term "treatment-resistant depression" is not frequently used in clinical settings. Terms such as "difficult-to-treat," "struggling with their condition," "complex needs," or "chronic" may be used instead.

TRD doesn't mean depression can't be treated. It means different treatments must be tried to find what works for that individual. Read on to learn about how to manage TRD.

Depressed man on bed with hand over his head

Songyuth Unkong / EyeEm / Getty Images

What Causes Treatment-Resistant Depression?

The cause of TRD isn't known, but research suggests risk factors may include:

  • Depressive episodes that are longer in duration: The longer a bout of depression lasts, the more opportunity for atrophy in specific brain regions (such as the hippocampus). Longer episodes can also result in behavioral and cognitive changes that may be harder to manage.
  • Severity: The most severe and the mildest forms of depression are both associated with a risk of treatment resistance.
  • Type of depression: TRD is more prevalent in bipolar depression than in MDD.
  • Symptom duration: Symptoms that don't improve within the first few weeks of treatment may be a sign of treatment-resistant depression.
  • Comorbid conditions: Anxiety (symptoms and/or disorder), personality disorders (especially avoidant and borderline), and other co-occurring conditions may affect treatment outcomes.
  • Age: Older-aged adults may respond less to treatment.
  • Biological factors: Genetics and biological factors may make some people respond more or less to some treatments than others.

While more studies are needed, research suggests inflammation may play a role in TRD.

How to Talk to Your Healthcare Provider

If you want to discuss your depression treatment plan with your healthcare provider, consider the following tips:

Before your appointment:

  • Determine what you want to get out of the appointment, such as a new treatment plan.
  • Write down any questions you want to ask so you can reference them during the appointment and not miss anything.

During your appointment:

  • Clearly state your concerns (don't "beat around the bush"—being open, honest, and direct helps your healthcare provider get an accurate picture of what's going on).
  • Take notes, or bring someone with you who can take down information while you discuss with your healthcare provider.
  • Be open to your healthcare provider's suggestions, but advocate for yourself too (if something doesn't sound right or you don't feel heard, say so).

After your appointment:

  • Book a follow-up appointment.
  • Follow your treatment as directed.

How Is It Diagnosed?

TRD isn't necessarily a diagnosis and typically isn't labeled as such by healthcare providers in your chart. It's more likely that the specific treatments or circumstances surrounding the depression will be noted and used for referrals.

Regardless of the terminology used, if a person does not see adequate results with treatment, other factors that may be playing a role need to be explored, such as:

  • Subtherapeutic doses: The dosage isn't high enough to be effective
  • Patient nonadherence: The person isn't following the treatment plan as directed
  • Intolerable adverse effects: Side effects that interfere too much with treatment
  • Incorrect diagnosis: Something else is causing the symptoms, such as thyroid disease

From there, the healthcare provider will gather similar information as they do for an initial diagnosis of depression and may do additional tests such as genetic testing or brain imaging.

How Common Is Treatment-Resistant Depression?

Rates vary depending on the study, but approximately 30% of people with MDD experience TRD. TRD affects about 1.1% of the general U.S. adult population.

Treatment Options

Several treatments have effectively treated TRD, with more potential options being studied.


Typically, the first medications prescribed for MDD are selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).

If the first prescribed medication is insufficient, switching to another class of antidepressants may prove effective. Switching to another medication within the same class may also be tried, but there is less evidence of success for switching within the same class.

If SSRI and SNRI options have been exhausted, other antidepressants such as tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) may be tried.

Other Medications

Medications other than antidepressants may be prescribed, often combined with an antidepressant (augmentation or adjunctive therapy). These may include:

  • Lithium (a naturally occurring salt)
  • Second-generation antipsychotics (SGAs)
  • Triiodothyronine (T3) (thyroid hormone)

In 2019, the Food and Drug Administration (FDA) approved Spravato, an esketamine nasal spray for use, along with an oral antidepressant for treating TRD. It is available through a restricted distribution system under a Risk Evaluation and Mitigation Strategy (REMS). It is administered in a certified medical office under the supervision of a healthcare provider.


Psychotherapy (talk therapy) can be used on its own but is often combined with other treatments, such as medication.

As with medication, some psychotherapy models may work well for a person, while others are less effective. Trying different types of psychotherapy may be necessary to find a fit.

Psychotherapy may be helpful when addressing comorbid conditions along with depression.

Psychotherapies that may be used to treat TRD include:

  • Cognitive behavioral therapy (CBT): Focuses on identifying distorted thought processes and behaviors and learning to change them into healthy, productive ones
  • Dialectical behavioral therapy (DBT): A modified version of CBT that includes mindfulness skills, distress tolerance, interpersonal effectiveness, and emotion regulation
  • Interpersonal therapy (IPT): Focuses on interpersonal relationships and social interactions
  • Intensive short-term dynamic psychotherapy (ISTDP): Uncovers and confronts past and present conflicted thoughts and emotions

Vagus Nerve Stimulation

The vagus nerve is the tenth cranial nerve. It runs from the brain, through the face and thorax, to the abdomen. It's believed that stimulating the vagus nerve alters certain networks of the brain, which can treat psychiatric problems.

Vagus nerve stimulation (VNS) involves an implanted pulse generator device inserted under the skin of the chest that connects to an electrode attached to the vagus nerve in the neck. This system sends electrical signals to the vagus nerve.

VNS is approved by the FDA for use in people with depression who have not responded to four or more medications.

For some people, this treatment shows a quick response. For others, effects start to emerge after about three months of treatment.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is an established, effective treatment for TRD.

ECT is a short procedure performed under general anesthesia in which a series of high-frequency electrical pulses are delivered to specific areas of the brain. It is usually performed on an outpatient basis.

ECT for TRD typically involves two to three sessions a week for a total of about six to 18 sessions.

Stigma and false information about ECT are often spread, but ECT is considered safe and is reported to be the most effective treatment for TRD.

Alternative Treatments

Promising treatments for TRD are currently being studied.

For example, the relationship between cerebral folate deficiency (CFD) and depression and how it affects the production of the neurotransmitter serotonin is being explored. Studies on treatment with folic acid are being conducted.

Other Steps You Can Take

In addition to professional treatment, there are other measures you can take to help manage your depression symptoms.

Consider Pharmacogenetic Testing

Pharmacogenetics (also called pharmacogenomics) explores the effects genes have on how the body responds to certain medications.

Genes may play a part in how medications affect different people, even when the medication type and dosage are the same.

Pharmacogenetic testing may be useful in determining which medications and dosages might work best for you and the likelihood of severe side effects from certain medications.

Make Healthy Lifestyle Choices

Making healthy lifestyle choices can help you feel better physically and mentally. Try to:

  • Get some physical activity
  • Practice good sleep hygiene, and establish a sleep routine
  • Eat nutritious foods and regular meals
  • Connect with others, such as talking with loved ones or joining a support group
  • Wait until you are feeling better before making big life decisions
  • Avoid substances such as alcohol, nicotine, and recreational drugs

Stick to Your Treatment Plan

Make sure you understand your treatment plan and that it is something you can stick with. Don't be afraid to ask your healthcare provider or mental health professional questions. Let your healthcare provider know if you don't think something is doable for you.

Once a plan is in place, follow it as directed. Your healthcare provider can give you an idea of how long you can expect to wait to see results. If you haven't noticed an improvement within that time frame, check back in with your healthcare provider.

Help Is Available

If you are having suicidal thoughts, contact the National Suicide Prevention Lifeline at 1-800-273-8255 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.


While there's no formal definition of treatment-resistant depression, it typically refers to depression that has not responded adequately to two or more treatments with medication. Despite the name, TRD is treatable; it's just a matter of finding which treatment works.

TRD may be treated with measures such as medication, psychotherapy, vagus nerve stimulation, and ECT. More treatments for TRD are currently being studied.

A Word From Verywell 

Depression can be a debilitating condition. If you feel your depression symptoms are not well-managed with your current treatment plan, talk to your healthcare provider or mental health professional about other options. Together, you can discover the best treatment option that works for you.

Frequently Asked Questions

  • What percentage of people with depression are treatment-resistant?

    Rates vary depending on the study, but an estimated 30% of people with MDD experience TRD.

  • Why don’t antidepressants always work?

    It can be challenging to pinpoint an exact reason why an antidepressant isn't effective for an individual, but some theories as to why a certain antidepressant may work for one person and not another include:

    • Problems with making serotonin that influence the effectiveness of medications involving serotonin reuptake control.
    • Neurobiological differences that affect how a person responds to certain treatments
  • How can you tell if your antidepressants are not working?

    Early signs that antidepressants aren't working effectively are similar to symptoms that occur with the onset of depression. These may include:

    • Low or "down" mood
    • Changes in appetite or sleep
    • A decrease in socializing
    • A loss of interest in previously enjoyable activities
12 Sources
Verywell Health 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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  7. U.S. Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic.

  8. Markowitz JC, Wright JH, Peeters F, Thase ME, Kocsis JH, Sudak DM. The neglected role of psychotherapy for treatment-resistant depression. AJP. 2022;179(2):90-93. doi:10.1176/appi.ajp.2021.21050535

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By Heather Jones
Heather M. Jones is a freelance writer with a strong focus on health, parenting, disability, and feminism.