Symptoms of Treatment-Resistant Depression

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Less than half of patients with depression can achieve full remission with the first treatment they receive, and approximately one-third of patients experience treatment-resistant depression (TRD).

Treatment-Resistant Depression

Treatment-resistant depression describes depressive symptoms that continue even after the treatment should have started working. Even if the treatment does have some effect, you might still be characterized as resistant if your depressive symptoms don’t reduce in severity by at least half. TRD can also refer to cases where a treatment that initially worked loses effectiveness, resulting in depressive symptoms returning even with ongoing treatment.

Signs and Symptoms

While multiple treatment approaches are effective, no single treatment is universally effective for all patients. So, if you're beginning treatment for your depression, the process may involve some trial and error.

If you discover that various treatments are not working for you, you likely have treatment-resistant depression.

Treatment-Resistant Depression Symptoms

The primary symptoms of TRD include:

  • Depressive symptoms persist even after the treatment should have started working
  • Symptoms decrease somewhat with treatment, but not enough to substantially improve quality of life
  • A treatment that used to work has lost effectiveness with ongoing treatment
  • Frequent relapses or recurrences of depression, even if treatment does result in a brief or partial remission
  • An increase in dosage does not cause any change in your depressive symptoms
  • This lack of response occurs even though you are following the treatment plan as prescribed

Experiencing these signs and symptoms with any treatment is enough for your doctor to determine that your depression is resistant to that particular treatment.

Complications & Comorbidities

Little is known about why some patients respond to certain treatments but not others or why some don’t seem to respond to most available treatments. However, researchers have pinpointed some risk factors that make someone more likely to experience TRD.

Those risk factors include:

  • Being assigned female at birth
  • Being over the age of 45
  • Low socioeconomic status
  • Lack of social support or family networks
  • Having a comorbid medical condition
  • Having a comorbid psychiatric disorder

In addition, patients with certain forms of depression are more likely to be nonresponsive to one or more treatments.

What Else Can Increase Your Risk of TRD?

Depression characteristics that increase your risk of TRD include:

  • Psychotic symptoms like delusions or hallucinations
  • Longer lasting episodes
  • More frequent episodes

Treatment-Resistant Depression and Misdiagnosis

TRD is largely defined by whether or not a patient responds to depression treatments. So it’s easy to overlook that, in some cases, they might not be responding simply because the diagnosis is wrong.

People Diagnosed With TRD May Have Been Misdiagnosed

If a patient with undetected asthma is not responding to allergy medication, diagnosing them with “treatment-resistant allergies” wouldn’t address the underlying source of their breathing problems. They did not receive the proper treatment.

Emerging research suggests that many TRD patients might not respond to treatment because they either have an undetected comorbid condition or a different condition altogether that was wrongly diagnosed as major depressive disorder. One study found that 34% of participants with TRD met the diagnostic criteria for ADHD, for example.

Another systematic review found that up to 50% of TRD patients met the criteria for bipolar spectrum disorder. ADHD and bipolar disorder are unlikely to respond to antidepressants, but these disorders do respond to other medications.

Chronic Depression vs. Acute Depression

A TRD diagnosis is based on viewing depression as an acute condition, meaning the treatments you try in that trial-and-error phase are meant to be used for a short period and lead to full remission, sort of like taking a short course of antibiotics to fully eliminate an infection.

Understanding Depression as a Chronic Illness

But some clinicians argue that TRD might be partially explained by the fact that some cases of depression are better understood as a chronic illness rather than an acute condition.

"Difficult-to-Treat" Depression

Often preferring to call it “difficult-to-treat depression" (DTD), this chronic illness approach recognizes that it may be harder to treat, but it’s not impossible. It just requires a different understanding of what successful treatment outcomes look like and what a treatment plan should focus on.

Specifically, the DTD approach shifts the goal from full remission after acute treatment to optimal symptom control and overall improvement in quality of life. As a result, a long-term and holistic treatment approach is required. This type of treatment includes:

  • Addressing stressors in your environment or relationships that could trigger episodes
  • Regularly re-screening for potential underlying comorbidities or health problems that might be causing or exacerbating your depressive symptoms
  • Using a mixture of acute treatments and long-term management techniques that can turn the illness into a more easily treated depression

Instead of plain trial and error, the approach emphasizes frequent review to ensure no diagnosis is missed and no potentially beneficial treatment is overlooked.

Whether your depression is a chronic or an acute condition, the DTD approach can be helpful because it accounts for more of the complexities involved in treating and managing depression.

Can Treatment-Resistant Depression Be Treated?

Yes, treatment-resistant depression can be treated. TRD means you aren’t responding to first-line depression therapies like antidepressants.

Still, various treatment approaches are available, including medication, psychotherapy, and even lifestyle changes.

The growing body of research on the link between TRD and undiagnosed conditions like ADHD or bipolar spectrum disorder should also be considered an encouraging sign. When a patient can get a correct diagnosis and switch to a more appropriate treatment plan for that condition, it often improves the depressive symptoms in the process.

If you’ve run through multiple trials of antidepressants without success, that doesn’t mean you depression is untreatable. It just means you and your doctor might need to reevaluate your diagnosis and expand your scope of treatment options.

Is There Hope for Treatment-Resistant Depression?

After multiple trials of different treatments with no success, it’s easy to feel hopeless and “incurable.” But there is still a path forward, even if you haven’t had any luck with antidepressants.

One study on the long-term outcomes of TRD found that even with existing treatment options, most TRD patients can eventually achieve improved outcomes, whether full remission, partial remission or prolonged symptom-free periods between episodes.  

The biggest predictor of a positive outcome for patients with TRD was having social support. So if you have friends or family that you feel safe reaching out to, do that. If you don’t, consider joining a support group to surround yourself with people who understand what you’re going through.

Depression Resources

Here are some resources to help you find online and local depression support groups:

Ketamine Treatment

Outside of current treatment approaches, some emerging approaches have demonstrated especially hopeful signs of being able to treat TRD. Among those, ketamine may be the most promising.

Several studies on TRD patients found that a ketamine infusion could significantly reduce depression, including suicidal ideation, in as little as three hours after treatment. The improvements lasted an average of 5 to 7 days.

8 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.
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By Rachael Green
Rachael is a New York-based writer and freelance writer for Verywell Mind, where she leverages her decades of personal experience with and research on mental illness—particularly ADHD and depression—to help readers better understand how their mind works and how to manage their mental health.