man with depression holds head in hand

It is no secret that depressive disorders can undermine a person’s ability to live a productive and satisfying life. The impact is even greater for people whose symptoms have not responded to prior treatment efforts.

According to two recent studies, the negative effects of treatment-resistant depression (TRD) may include longer depressive episodes, a greater likelihood of developing a co-occurring mental health concern, and an increased risk of early death.

What Is Treatment-Resistant Depression?

Before we delve into the dangers linked to TRD, let’s take a moment to define treatment-resistant depression.

At first glance, the term “treatment-resistant depression” appears to be straightforward and easily understandable. It just means depression that hasn’t responded to treatment, right?

In a general, informal sense, this is correct. But researchers, clinicians, and other experts typically try to avoid general and informal terminology.

Mental health professionals in the United States usually look to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for criteria to define mental health concerns. However, the DSM-5 does not include an entry for TRD. This has led to an ongoing discussion among experts about how to identify if someone has treatment-resistant depression.

To provide a bit of clarity, let’s break the term down into its component parts:


In the context of TRD, depression refers to major depressive disorder. This form of depression is characterized by severe, potentially debilitating symptoms that last for at least two weeks at a time.


Depression is commonly treated with a combination of medication and therapy. Most experts consider someone to have treatment-resistant depression if their symptoms have not improved after taking at least two antidepressants for a reasonable amount of time.


There is no standard, universally agreed-upon measure to determine if someone has or has not responded well to antidepressants. In most cases, identifying resistance to treatment is a matter of a professional and a patient working together to assess the patient’s progress toward their treatment goals.

Though no standard definition yet exists, it’s safe to say that many clinicians would describe treatment-resistant depression as major depressive disorder with symptoms that have not improved after a person has completed at least two courses of treatment with different antidepressants.

Now that we have established a working understanding of TRD, let’s look at a few studies that suggest a connection between this mental health disorder and an increased risk of early death.

Increased Hospitalization, Decreased Life Expectancy

In December 2022, the journal JAMA Psychiatry published a population-based observational study on how treatment-resistant depression impacts patient outcomes and the utilization of healthcare resources. This study was conducted by a team of Swedish researchers who were led by Johan Lundberg of the Karolinska Institute in Stockholm.

General Study Parameters

  • The team reviewed the records of 145,577 patients aged 18 and above, including 12,765 who met the criteria for treatment-resistant depression.
  • This data included all recorded major depressive episodes among adults in the Stockholm area from Jan. 1, 2012, to Dec. 31, 2017.
  • The team matched each recorded episode of treatment-resistant depression with up to five non-TRD episodes involving individuals of similar age, gender, socioeconomic status, and depression history.

After analyzing the data and comparing treatment-resistant depression patients with treatment-responsive (or non-TRD) patients, the team drew the following conclusions:

  • Patients who had episodes of treatment-resistant depression were more likely to also have anxiety, obsessive-compulsive disorder OCD), and other co-occurring mental health concerns.
  • Patients who had TRD were more likely to also struggle with sleep disorders, substance abuse, and self-harm.
  • Patients with TRD were more likely to have been treated with psychotherapy, add-on medications, and electroconvulsive therapy (ECT).
  • Patients with treatment-resistant depression averaged 50% more outpatient physician visits.
  • Patients with a history of TRD spent three times more days in inpatient care than did those who had non-TRD major depressive disorder.
  • The severity of a person’s symptoms at the time they were diagnosed with major depressive disorder was the most important factor in determining which patients would struggle with TRD.

In addition to these results, the Swedish research team also discovered that the all-cause mortality rate among people who have treatment-resistant depression was 23% higher than among the non-TRD group. This gap is partially explained by higher rates of suicide and self-harm among people with TRD, but those factors alone do not account for the full difference.

Significantly Shorter Survival

The Swedish team’s findings of an increased all-cause mortality rate among people with treatment-resistant depression were consistent with the results of a U.S. study that appeared in the September 2019 edition of the Annals of General Psychiatry.

In the background section of this study, the research team – which was led by Gang Li of Janssen Research and Development – noted that a previous meta-analysis found that people with major depressive disorder have a 50% greater risk of mortality than do people who don’t have depression. This meta-analysis did not differentiate between TRD and non-TRD.

Factors That Contribute to Elevated Mortality Rate

  • Depression has been linked with physiological changes such as “peripheral inflammation, oxidative stress, and cardio-metabolic conditions that contribute to the development of chronic somatic diseases.”
  • People who struggle with depression are more likely to engage in unhealthy behaviors such as smoking, following a poor diet, adopting a sedentary lifestyle, and failing to adhere to medical advice.
  • Some people develop co-occurring depression while also living with a chronic medical condition.

In their study, the U.S. team focused on determining if the mortality rate is even higher among people whose symptoms have not responded to treatment with at least two antidepressants.

Notable Study Features

  • The team analyzed data from 355,942 patients with major depressive disorder, including 34,176  with treatment-resistant depression.
  • This information, taken from a U.S. claims database, included people with depressive episodes between Jan 1, 2008, and Sept. 30, 2015.
  • The patient group in the U.S. study was more than twice as large as in the Swedish study. It also involved a slightly larger percentage of patients with TRD (9.6% vs. 8.76%).

An analysis of this data revealed that people within the TRD subgroup had “significantly shorter” survival time and “significantly higher” all-cause mortality than did study subjects whose depression improved after treatment.

Of course, these factors don’t explain why people with TRD have such a significantly greater risk of death when compared with people whose symptoms have eased following treatment. The research team theorized that factors such as the following may contribute to this increased risk:

  • Within the population of people who have depression, those with TRD are more likely to have longer and more intense depressive episodes.
  • People with TRD have a greater likelihood of suicide, both during depressive episodes and at times when their symptoms are relatively mild.
  • Treatment-resistant depression may lead to lifestyle changes that increase a person’s risk for physical health concerns, while simultaneously impairing the individual’s ability to effectively manage these concerns.

“In totality, our findings add to the literature suggesting the potential importance of helping patients with depression manage their symptoms and exit an episode,” the team wrote, “and TRD patients face greater hurdles in achieving these goals.”

Help for Treatment-Resistant Depression

If you or someone that you care about have been struggling with treatment-resistant depression, please know that effective assistance is available. Crownview Psychiatric Institute specializes in helping adults impacted by complex mental health concerns, including TRD.

At our center in San Diego, California, patients follow customized treatment plans that incorporate medication, multiple forms of therapy, a dynamic array of adjunct services, a vibrant education program, and comprehensive wraparound support. Throughout a patient’s time with us, they also benefit from our innovative community-like environment.

To learn more about our services for people who have treatment-resistant depression, or to get answers to any questions you have about any aspect of our programming, please either visit our Contact page or call us at your earliest convenience.