Scientists Call For More Research on Treatment-Resistant Depression

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Key Takeaways

  • Up to 30% of adults diagnosed with major depressive disorder do not feel better when they take the medications that are typically used to treat it; what's known as treatment-resistant depression (TRD).
  • There has not been a standard definition or way of diagnosing TRD, which has made it hard for doctors to spot it—let alone treat it—in their patients.
  • To address the problem, an international team of researchers has come together to define the depressive spectrum—from major depressive disorder to partially-resistant depression and treatment-resistant depression.

In a new report published in the journal Molecular Psychiatry, researchers from all over the world have proposed a more comprehensive and clear definition of treatment-resistant depression (TRD).

The group has also called for more research on how the condition can be better identified and treated and hope to encourage more people to talk about depression.

Why Define TRD?

Having a definition that can be widely used and understood is important on several levels. For one, it matters to the scientists that are designing clinical trials for new medications and other potentially effective treatments for TRD.

A clear definition of TRD also helps clinicians who work with people who might have the condition and gives them a framework for diagnosing the condition—a crucial first step in making sure that people get treatment.

“My kind vision for what happens in 50 years —and I hope in 20 years, maybe even within my working lifetime—is having a way to personalize treatment to the individual patient exactly as we're doing for cancer,” Carmine Pariante a professor at the Institute of Psychiatry, Psychology, & Neuroscience of King’s College London and lead author of the recent study, told Verywell.

Personalized care might include biomarkers (which are measured in a sample of a patient's blood), brain scans, and genetic data, which can help doctors and mental health professionals figure out which patients will likely respond well to treatment for depression and which might not.

Once providers had a sense of which patients might have depression that is not likely to respond to the usual treatments, they can start brainstorming different ways to help them.

“Perhaps two antidepressants together or an anti-inflammatory and antidepressant, a psychedelic; whatever is going to be the correct drug for that person,” said Pariante. “I think that would really make a big difference between what we do now and what we do in the future.”

What Is TRD?

Major depression, a mood disorder that leads to debilitating, persistent feelings of sadness and a lack of interest in their daily lives, is a leading cause of disability worldwide. However, as many as 30% of adults with the condition do not respond to the medications that are typically prescribed to treat it.

Carmine Pariante

There's no single validated biomarker that says 'you are treatment-resistant, you're not treatment-resistant,' because it's not a yes and no condition.

— Carmine Pariante

There are a few reasons that some people are helped by standard depression treatments and others do not. We all have different bodies, brains, and experiences—that means that no two people will have the same response to the many ways to treat depression.

Another reason has less to do with the individuals that have depression and more to do with how the diagnosis is talked about and understood; for example, the criteria for defining and treating the condition.

“There's a big problem of patients who are not responding to currently available medication,” said Pariante. “Around one out of two—so only 50%—of patients respond to the first antidepressant that is prescribed, and maybe two out of three respond to the second or third antidepressant [that is tried].”

There's still "a core 25% of patients who don't respond to available medication, there's really a need to develop medication for this target population,” according to Pariante, who explained that ideally, such research would take the form of a trial in which multiple medications are tested at the same time in a collaborative way until they work (a “platform trial").

TRD Research Gaps

In the recent report, more than 60 scientists came together to discuss and look over the current description of TRD and draft new criteria for the condition.

As the experts collected data, they found that:

  • Only about one-third of the studies on TRD actually enrolled people who have been resistant to at least two antidepressant approaches.
  • Only one in five studies enrolled people who have had taken the proper amount (dosage) of medication and for the right amount of time (duration).

Without agreement on what the condition is, how can providers figure out which patients are considered treatment-resistant?

“These people exist from a clinical point of view, and they exist also from a biological point of view," said Pariante. "There's something in the way their body, or their brain, responds to depression."


It's also possible for people to get helped somewhat by a depression treatment, in which case they are not fully treatment-resistant. Instead, they are said to have partially-resistant depression (PRD).

The experts concluded that criteria for diagnosing PRD versus TRD should be:

  • To classify a person as having PRD, a person should have more than 25%—but less than 50%—of a reduction in symptoms after using one type of antidepressant.
  • To classify a person as having TRD, they should have less than 25% of a reduction in symptoms after trying at least two different types of antidepressants. TRD is also a matter of timing. For example, if a person is unresponsive to treatment within a single bout of depression or chronic depression.

Not Just Medication

TRD includes the word “treatment” because there are several ways to help people with depression, such as medication and psychotherapy. The experts said that all of the options should be taken into account, not just medication.

Carmine Pariante

There's something in the way their body, or their brain, responds to depression.

— Carmine Pariante

“I think that the concept of resistance—or response, which is kind of the inverse concept—is a continuum in a way,” said Pariante. "So, what has always happened in medicine is that you kind of create an arbitrary cutoff on a continuum spectrum of people that, you know, go from people who improve very well and quite quickly, up to the people that don't improve at all.”

Pariante said that the threshold on the continuum has been moving a little bit in different studies, “because, at the moment, there's no single validated biomarker that says 'you are treatment-resistant, you're not treatment-resistant,' because it's not a yes and no condition.”

Precision Leads to Progress

Armed with a clear definition of TRD, the next step is standardizing and innovating how providers can diagnose it. Experts are pushing for a more holistic and data-driven approach (which combines biological information like blood samples and brain scans) to look for biomarkers for depression.

Pariante added that TRD patients have real changes in their inflammatory biomarkers, and "if you measure biomarkers of inflammation—for example, c-reactive protein, or other biomarkers that are activated in under condition of metabolic dysfunction or infection—a treatment-resistant depressed patient looks very much like a patient with diabetes or coronary heart disease, even if they actually don't have diabetes or coronary heart disease."

While new potential treatments for depression like psychedelics, anti-inflammatory medications, and brain stimulation techniques are promising, Pariante said that more research is needed to better understand which options will work in a specific group of people with depression.

For the past 20 or 30 years, Pariante said that antidepressant research has been driven by the same kind of data. For example, medication research often builds on a previous medication and improves it and its side effects, but is always looking to tackle the same problems.

“Antidepressants have just been copies of previous medication, always around the same idea of inhibiting serotonin or stimulating noradrenaline functions," said Pariante. "So, kind of stimulating the function of neurotransmitters that regulate mood. But ecologically, there were very few changes."

The future might look different, though. Pariante said that now, "scientists are kind of starting with biological abnormalities and this research can only be improved by having a more cohesive homogenous group of people to study and test medication with.”

What This Means For You

If you or someone you know is struggling with depression and isn't sure where to get help, call SAMHSA’s National Helpline, 1-800-662-HELP (4357). It's confidential, free, and runs 24-hour-a-day, 365-day-a-year. It's available in English and Spanish.

If you call this helpline, they can give you referrals to local treatment centers, support groups, and other organizations.

2 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.
  1. Sforzini L, Worrell C, Kose M, et al. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trialsMol Psychiatry (2021). doi:10.1038/s41380-021-01381-x

  2. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directionsPatient Prefer Adherence. 2012;6:369-388. doi:10.2147/PPA.S29716

By Sofia Quaglia
Sofia Quaglia is a science and health writer based between Italy, the United Kingdom, and the United States.