man with head in hands from depression

The long-term consequences of treatment-resistant depression (TRD) can be significant and cause major disruption in a number of important life domains, including primary relationships, work, academic achievement, and the typical activities associated with optimal daily functioning. However, a new generation of therapies may help people diagnosed with treatment-resistant depression, which is defined as major-depressive disorder (MDD) with symptoms that don’t improve after two attempts at treatment with at least two different types of antidepressant medication.

This article discusses the consequences of treatment-resistant depression as identified in a study published in December 2022 called “Association of Treatment-Resistant Depression With Patient Outcomes and Health Care Resource Utilization in a Population-Wide Study.” We’ll begin by sharing the latest prevalence data on major depressive disorder (MDD) and treatment-resistant depression (TRD), then share the results of the study, and close with information on the new generation of therapeutic approaches that can help people diagnosed with major depressive disorder and/or treatment resistant depression (MDD and/or TRD).

Depression, Depressive Episodes, and Treatment-Resistant Depression: Facts and Figures

The World Health Organization (WHO) identifies depression and depressive disorders as the second most common mental health condition(s)  in the in the world after anxiety and anxiety-related disorders.

They report the following prevalence of depression around the globe:

  • 280 million people worldwide:
    • 3.8% of all people
    • 5.0% of adults over age 18
    • 5.7% of adults over age 60

In the United States, like the rest of the world depression and depressive disorders are also the second most commonly diagnosed mental health condition(s), after anxiety and anxiety disorders.

Data published by the National Institute of Mental Health (NIMH) indicates the following prevalence of depression in the U.S. in 2021.

Major Depressive Episode in 2021

  • Adults 18+ total: 8.3%
    • 21 million
  • Adults 18-25: 18.6%
    • 6.2 million
  • Adults 26-49: 9.3%
    • 9.5 million
  • Adults 50+: 4.5%
    • 5.3 million

Major Depressive Episode With Severe Impairment in 2021

  • Adults 18+ total: 5.7%
    • 14.5 million
  • Adults 18-25: 13.3%
    • 4.4 million
  • Adults 26-29: 6.5%
    • 6.6 million
  • Adults 50+: 2.9%
    • 3.4 million

In these statistics, major depressive episode (MDE) serves as a proxy for diagnosis of major depressive disorder, as the criteria for both are similar enough to make valid comparisons. Studies published here and here show that between 15 and 30 percent with MDD have treatment resistant depression (TRD). When we do simple calculations with the figures above for people who reported MDE, we find that in the U.S. in 2021, between 3.1 and 6.2 million people had treatment-resistant depression.

Now let’s look at the study we introduce in the introduction.

Treatment-Resistant Depression: Outcomes from a Population-Wide Study

The study that has our attention was conducted at the Karolinksa Institute in Sweden and used records collected between 2010 and 2017 from a group of patients the Stockholm MDD Cohort. To identify patterns and trends among patients with MDD and TRD, researchers examined data collected from 158,169 treatment episodes – from a total of 145,577 patients – related to major depressive disorder (MDD) that required acute medical care in an inpatient hospital setting.

The researchers analyzed the data to answer the following questions:

How many patients with MDD had TRD?
How long did it take a patient with MDD to meet criteria for TRD?
What types of treatment did they attempt before TRD diagnosis?

In addition to answering these questions, the researchers identified and analyzed outcomes related to the following measures for people with TRD:

  • Days spent in inpatient care
  • Days of work lost to MDD/TRD
  • Presence of comorbid mental health conditions
  • Incidence of self-harm
  • Rates of all-cause mortality

Let’s take a look at what they found.

TRD Study: The Results

Among the 145,577 patients with MDD:

  • 12,793 met criteria for TRD (11%)
  • Time from first MDD episode to TRD diagnosis: 552 days (294-932).
  • Most common medication used: selective serotonin reuptake inhibitor (SSRI)
  • 2% of patients with MDD engaged in psychotherapy before TRD diagnosis

Those are the big picture results. Of note in this data is the relatively low total of MDD patients with TRD. In this sample set, the prevalence of TRD was around 11 percent, which is roughly a third of most previous research, which estimates the rate of TRD among people with MDD as 30 percent.

With regards to the second set of outcomes, researchers compared data from patients with TRD to patients without TRD. They found the patients with TRD experienced:

  • More time in inpatient care:
    • 9 days for people with TRD
    • 3 days for MDD with no TRD
  • More lost workdays:
    • 3 days or people with TRD in the year following diagnosis
    • 7 for MDD with no TRD in the year following diagnosis
  • Higher rate of comorbid psychiatric conditions, including:
    • Anxiety
    • Stress-related disorders
    • Obsessive-compulsive disorder
    • Sleep disorders
    • Substance use disorder
  • Increased incidence of self-harm:
    • People 4 times more common in people with TRD compared to typical MDD
  • Increased mortality rate:
    • 7/1000 person-years at risk for people with TRD
    • 7/1000 person-years at risk for people with MDD

Finally, the researchers also analyzed the data for one more thing: a way to accurately predict TRD among people with MDD upon initial diagnosis. We’ll report on that now, then discuss treatment options for people with TRD.

What Predicts TRD in People with MDD?

Previous research identifies several risk factors, or conditions that, if present, may predict the onset of treatment resistant depression. The commonly accepted risk factors include:

  • Older age
  • Psychiatric comorbidities
  • Length of MDD symptoms
  • Early age at onset
  • History of emotional, physical, or sexual abuse and treatment-related factors

However, the researchers found that none of these factors predicted the onset of TRD. Instead, one thing factor was common to patients who developed TRD: the severity of symptoms at initial diagnosis. Here’s how Dr. Johann Lundberg, one of the principal authors of the study, describes this finding:

“We’re talking about a patient group with a substantial health care consumption that might be identified earlier than today by increasing the use of symptom severity rating scales. Going by the results of the study, their care and treatment could be improved if their physician replaced ineffective treatments more rapidly and more often used treatments recommended for treatment resistant depression.”

That brings us to the final section of this article: effective approaches to the treatment and management of symptoms for people with TRD.

Treatment-Resistant Depression: What Works?

In recent years, the Food and Drug Administration (FDA) approved two new therapeutic approaches for treatment-resistant depression: transcranial magnetic stimulation (TMS) and psychedelic therapy. We’ll describe those new approaches now, starting with TMS.

Transcranial Magnetic Stimulation

TMS is the use of focused electromagnetic impulses, directed at specific areas of the brain, to relieve the symptoms of depression. It’s similar to a type of technology most people know about: magnetic resonance imaging (MRI). An MRI works by generation electromagnetic impulses, directing them at an area of the body, and observing how those impulses “bounce back.” They use the information to create a picture of the target body part.

With a TMS machine, there is no need to measure the bounce back, which means the machine is much smaller than an MRI machine. Clinicians place a coil or special helmet on the patients head, and direct the electromagnetic impulses at brain areas associated with depression. The impulses stimulate the brain area, and the stimulation itself is the treatment.

Evidence shows that TMS reduces symptoms of TRD in 50-60 percent of patients, and can lead to full remission of symptoms in 30-40 percent of patients with TRD. To learn more about TMS, please visit our website and read this page:

Transcranial Magnetic Stimulation

Next, we’ll talk about psychedelic therapy.

Psychedelics: Ketamine and Spravato®

Ketamine and Spravato® are two different types of medication for treatment-resistant depression. Ketamine was originally developed as an anesthetic, but scientists realized that at low doses, it can be an effective treatment for all types of depression, and one of the only medications that’s effective for treatment-resistant depression.

There are three ways to administer ketamine:

  • Via intravenous infusion. This is called IV Ketamine treatment.
  • Through an orally ingested liquid. This is known as oral administration.
  • With a nasal spray called Spravato®. Patients self-administer a nasal spray, exactly as they might self-administer a nasal spray for allergies.

In most cases, patients receive several doses of ketamine or Spravato® over a period of one to two months. Patients who receive ketamine treatment often receive infusions over 2-3 weeks, then receive additional infusions based on need, as determined by their treatment team. Patients who receive Spravato® treatment may receive weekly doses for 8 or 9 weeks, and tailor additional doses as needed, as determined by their treatment team.

To learn more about psychedelic therapy with ketamine or Spravato®, please visit our website and read this page:

Ketamine and Spravato®

Given the consequences of treatment-resistant depression, these new therapies – as well as the information we shared from the study in Sweden – are important developments for people with TRD.

Hope For Patients with TRD

We presented one item in the data above without comment: the increase in all-cause mortality for people with TRD, as compared to people with MDD but without TRD. Again, we’ll quote the lead researcher, Dr. Lundberg:

“We found that the treatment-resistant group used outpatient resources twice as much, had twice the amount of sick leave, spent three times the number of days in hospital and had a 23 percent higher mortality rate than patients without treatment-responsive depression.”

That’s not an exaggeration or an aberration in the data: in this study, people with TRD died prematurely at a rate 20 percent greater than people with MDD. That’s a sobering finding – and one that foregrounds the importance of effective treatment for TRD, such as TMS and psychedelic therapy. What that tells us is that these new treatments may not only improve the lives of people with TRD, but in some cases, these new treatments may also save their lives. That’s a major development – and that’s why we’re committed to offering these new, cutting edge therapies to patients who seek help and support for major depressive disorder or treatment-resistant depression.