We all have personal ways of describing depression. Numbness. Psychological torture. A negative voice that won’t stop ringing inside your head no matter how many times you tell it to shut up. But for those battling treatment-resistant depression (TRD), a single word might come to mind: trapped. TRD describes depression that has failed to respond to at least two different antidepressant treatments.

It’s surprisingly common—up to one-third of depressed patients are considered treatment-resistant. For those affected, finding a treatment is an adventure no one asked for. It involves months of trial and error and could eventually lead to a more intimidating alternative therapy such as ketamine or electroconvulsive therapy (ECT).

But before venturing down that path, it’s crucial to make sure you actually have TRD (which is easy to misdiagnose). “If depression isn’t treated correctly, it will look treatment-resistant,” says Alexander Papp, MD, psychiatrist at UC San Diego Health. “In some cases, it’s the treatment that’s the problem, not the depression.”

Determining If You Might Have Treatment-Resistant Depression

After 2-3 weeks of taking medication, did you notice any improvement?

You should see some improvement in your depression within the first few weeks of starting an antidepressant. But be patient—everyone’s brain is different. Most doctors recommend giving each medication 6-8 weeks to work fully and trying up to four antidepressants from different classes to find the right one for you.

How long have you been depressed?

People with a history of depression are likely to become treatment-resistant over time. Long episodes of depression can cause cognitive and behavioral changes that eventually become second nature. It’s also common for people who once had success on an antidepressant to experience a “poop-out” effect (or tachyphylaxis). Studies estimate that 25-30 percent of those on antidepressants will experience tachyphylaxis at some point.

How severe are your symptoms?

Doctors suspect that both ends of the depression spectrum—severe symptoms and mild symptoms–don’t respond well to antidepressants. This is because severe depression may be caused by a different type of biological imbalance than moderate depression, while mild depression benefits from the placebo effect as often as it does from medicine.

Are you anxious?

Depression and anxiety often go hand in hand. Worse yet, studies have found that when they do coexist, anxiety predicts a low rate of response to antidepressants.

Have you been diagnosed with bipolar depression?

People who have bipolar depression are more likely to be treatment-resistant than people with a major depressive disorder. While the connection isn’t completely understood, people with TRD are known to have some of the same distinct genetic risk markers as those with bipolar depression. This would influence the likelihood that someone would respond to an antidepressant.

How old are you?

The elderly are more likely to be affected by TRD. This could be because their depression has gone on longer and tends to be more severe. One study also attributed it to disability, functional decline, and a diminished quality of life.

Do you have a history of substance abuse?

While the relationship between TRD and substance abuse can sometimes be a question of the chicken or the egg, research often finds that the two are related. Many addictive substances cause changes in the brain (especially in the dopamine system) which can result in depression and affect the way the body receives antidepressants.

Do you experience chronic pain?

Links have been found between chronic pain and TRD. Injury sensory pathways are in the same brain regions as mood management. Because chronic pain induces stress for a prolonged period of time, it could be based on similar, maladaptive changes as depression.

Signs It’s Just The Medicine

Not adding up? You may not have TRD after all. Here are other reasons your medication might not be working.

  • You haven’t tried two or more antidepressants from different classes (SSRI and SNRI).
  • You were not prescribed the right dosage.
  • You haven’t been taking the medicine exactly as directed.
  • The side effects have been unpleasant, so you might have skipped a dose here or there.
  • You didn’t give each antidepressant trial the full 6-8 weeks.
  • You’re on another medication (like blood pressure, antibiotics, or steroid) that interferes with antidepressants.
  • You have a medical problem that mimics the symptoms of depression, such as hypothyroidism, sleep apnea, low blood pressure, nutritional deficiencies, chronic fatigue syndrome, and bipolar disorder.

If you do think you have TRD, there is hope. Check out this page to read all about potential treatment options for this tricky condition.

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Last Updated: Aug 17, 2020