We Need a Clearer Understanding of Treatment-Resistant Depression, Experts Say

young man sits on a bench looking sad

Gadiel Lazcano / Unsplash

Key Takeaways

  • More than a third of people with depression don't respond to antidepressants or other treatments.
  • However, there's still widespread uncertainty surrounding treatment-resistant depression (TRD).
  • Authors of a new study say the first step is to establish criteria for a universally recognized definition of TRD.

Antidepressants usually help to treat the symptoms of depression—but not always. Studies have found that treatment-resistant depression (TRD) affects around 30% of adults with major depressive disorder. 

However, there’s a huge amount of uncertainty around the concept of TRD, with no universally accepted definition for the condition. This makes it more difficult to address the characteristics of TRD, compared to cases of depression that do respond to initial treatments, says Aron Tendler, MD, board-certified psychiatrist and Chief Medical Officer of BrainsWay.

“There may be a difference between the definitions of treatment-resistant depression within research and those applied in practice,” Dr. Tendler adds. 

New research, published in Molecular Psychiatry, set out to establish new criteria to define the type of depression that doesn’t respond to medications and therapies. 

The Study in Detail

Despite the evidence that conventional treatments fail to improve depressive symptoms in approximately one-third of people, there is still uncertainty around concepts such as response, non-response, and partial response. There is also a lack of consensus around the concept of “adequate” antidepressant treatments

“This ambiguity is detrimental, particularly in research settings,” explains study author Dr. Luca Sforzini from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London. “Having ambiguous definitions for inclusion in clinical trials may imply that different studies on an equally defined condition (such as treatment-resistant depression, TRD, or partially responsive depression, PRD) may analyze different populations, and potentially different conditions.”

The researchers used the well-known Delphi Method to collect and summarize the views of over 60 experts in the field of depression, including clinicians, academicians, researchers, members of industry and regulatory agencies, and one person with lived experience. 

Dr. Luca Sforzini

We tried to take the first fundamental step to fully elucidate TRD and PRD and guide further research, by clearly defining these conditions.

— Dr. Luca Sforzini

“We aimed to gain consensus on the main uncertainties and gaps in knowledge to produce clear definitions of TRD and PRD for inclusion of participants in clinical trials,” Dr. Sforzini says. "Because of the importance of the subject discussed and the current lack of consensus guidelines, we feel that such a guideline was much needed.”

The report provides 25 consensus recommendations, based on the view supported by the largest number (more than half) of the experts, including definitions of both TRD and PRD. The report suggests that TRD should be defined after a minimum of two failed treatments (with “failure” defined as an improvement less than 25% in clinical scores, before and after treatment), with adequate dosing and duration (the minimal licensed dosage administered for at least four weeks) and different mechanisms of action. 

When it comes to PRD, this can be defined after a single treatment with adequate dosing and duration.

Understanding Depression

We may have come a long way in our understanding of depression and other mental health conditions, but we still have some way to go.

"There are many different clinical phenotypes of depression and these are probably related to different biological and molecular profiles," explains Dr. Sforzini. This means that a depression that “does not respond” (or “respond partially”) to treatments may have some intrinsic differences compared with “responsive” depression, with peculiar clinical, biological, and molecular features.

"Understanding these features may allow a better characterization of TRD and PRD, ultimately leading to novel discoveries for diagnosis, prevention, and treatment," Dr. Sforzini says. "We tried to take the first fundamental step to fully elucidate TRD and PRD and guide further research, by better defining these conditions."

The team's ultimate ambition is to provide clearer, more reliable research in this area, to advance tailored treatments and a "precision medicine" approach. "This, in turn, will finally help to deliver better care for people with depression," Dr. Sforzini says.

Managing Treatment-Resistant Depression

Patients living with treatment-resistant depression have been shown to respond positively to a number of options, says Dr. Tendler.

Electroconvulsive therapy (ECT) may be a scary prospect for many people, but it's actually highly effective in treating major depression. During the procedure, while the patient is under general anesthesia, a small amount of electrical current is passed through the brain to trigger a seizure. This affects brain activity in ways that lead to clinical improvement. "ECT is considered among the most effective treatments against depression and is used in severe cases of this condition," says Dr. Tendler. "That said, it's an invasive treatment, with possible side effects including short-term memory loss, causing many patients to balk at the thought of it."

Deep Transcranial Magnetic Stimulation, or Deep TMS™, is an FDA-cleared, noninvasive medical device treatment that uses electromagnetic pulses to stimulate brain structures found to be associated with several mental health conditions. "Deep TMS has been shown to be beneficial in cases of treatment-resistant depression due to its own combination of safety and efficacy," says Dr. Tendler. "More specifically, the treatment has been shown to offer symptom relief to those suffering from depression both as a standalone treatment or in addition to other forms of treatment, including medication."

Another FDA-approved option for treatment-resistant depression is vagus nerve stimulation, which relies on stimulating one of the body’s two vagus nerves, which connect the brain to several vital organs and systems. It's an invasive treatment, which includes implanting a small medical device under the skin and connecting it to the patient’s left vagus nerve. Possible side effects for this treatment include voice change and shortness of breath, Dr. Tendler notes.

What This Means For You

If your depression doesn't respond to the first couple of treatments, that doesn't mean it can't be treated. It may simply require a new approach. By working with your doctor, you can explore different options until you find the treatment plan that works for you.

7 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.
  1. Zhdanava M et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. The Journal of Clinical Psychiatry. 2021 March. doi:10.4088/JCP.20m13699

  2. Sforzini L et al. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials. Molecular Psychiatry. 2021 December. doi:10.1038/s41380-021-01381-x

  3. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-88. doi:10.2147/PPA.S29716.

  4. Serretti A. The present and future of precision medicine in psychiatry: Focus on clinical psychopharmacology of antidepressants. Clin Psychopharmacol Neurosci. 2018 Feb 28;16(1):1-6. doi:10.9758/cpn.2018.16.1.1

  5. American Psychiatric Association. What is ECT?

  6. Levkovitz Y, Isserles M, Padberg F, Lisanby SH, Bystritsky A, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry. 2015 Feb;14(1):64-73. doi:10.1002/wps.20199

  7. American Association of Neurological Surgeons. Vagus nerve stimulation.

By Claire Gillespie
Claire Gillespie is a freelance writer specializing in mental health. She’s written for The Washington Post, Vice, Health, Women’s Health, SELF, The Huffington Post, and many more.