As if depression wasn’t insidious enough, allow us to introduce you to its fickle, evil twin: treatment-resistant depression (TRD). A major depressive disorder, TRD describes depression that has failed to respond to at least two different antidepressant treatments. Anyone who has experienced depression knows how inescapable and hopeless it can feel. TRD compounds that problem, making it difficult for patients to find a treatment that offers lasting relief.

You might imagine that’s pretty rare, right? Wrong. Up to one-third of adults with major depression battle symptoms that don’t get better with treatment. Many people struggle to find the medication that’s right for them, while others never respond to your standard antidepressants. According to Alexander Papp, MD, psychiatrist at UC San Diego Health, only 30-35 percent of patients respond to the first antidepressant they’re prescribed.

What Are The Signs And Symptoms Of Treatment-Resistant Depression?

The number one sign of TRD is that you’ve tried multiple antidepressants as directed (no skipping doses!) and still aren’t feeling better.

“If you haven’t had an adequate response to antidepressant medication by about 10 weeks of treatment with the optimal dose, it’s probably worthwhile to request a change in your treatment plan,” says John H. Krystal, MD, McNeil Professor and Chair of Psychiatry at Yale. “This change might involve adding psychotherapy, an additional medication, switching antidepressants, or starting a neurostimulation treatment.”

Pay attention to:

  • A lack of response to antidepressants and psychotherapy treatments
  • Increasingly severe and longer episodes of depression
  • Brief improvements followed by a return of depression symptoms
  • High anxiety or anxiety disorder

Okay, But How Do I Know It’s Treatment-Resistant Depression?

TRD is easy to misdiagnose for a number of reasons. Doctors prescribe the wrong dose. Patients forget to pack their meds while they’re on vacation. People simply get frustrated and quit taking their pills. There are many scenarios that could cause someone to think an antidepressant isn’t working when it is (or could with minor adjustments).

“If depression isn’t treated correctly, it will look treatment-resistant,” says Papp. “In some cases, it’s the treatment that’s the problem, not the depression.”

So how do you know you’re really dealing with TRD?

  • You’ve figured out the right antidepressant and dosage. Unfortunately, there are no shortcuts here. While everyone’s personal threshold is different, most doctors recommend trying up to four antidepressants from different classes to find your perfect match. Typically, patients will start off with a selective serotonin reuptake inhibitor (SSRI)—such as Lexapro (escitalopram) or Zoloft (sertraline)—before moving to a selective serotonin and norepinephrine reuptake inhibitor (SNRI) like Cymbalta (duloxetine) and Effexor XR (venlafaxine). If neither does the job, it’s usually time for high level combination treatments. Keep in mind, each medicine takes six to eight weeks to work properly. That means up to eight months to properly diagnose TRD. (Yes, it’s a slog.)
  • Your other meds aren’t interfering. Even then, there are other reasons antidepressants might not work correctly. Papp points to additional medications as a common culprit. “Some medications—like blood pressure, antibiotics, or steroids—can speed up the enzymes that metabolize antidepressants too quickly,” he says.
  • You have a clean bill of health. Medical problems like hypothyroidism, chronic pain, hormone imbalances, and addiction can cause or worsen depression. If you’re not treating your depression’s underlying issues, then it’s sure to stick around no matter what medication you’re on.

What Causes Treatment-Resistant Depression?

There’s certainly no lack of theories explaining why so many people don’t respond to antidepressants, but it likely has to do with a fundamental misunderstanding of depression’s biology.

While some scientists believe depression is caused by low levels of happiness-signaling chemicals like serotonin and norepinephrine, others claim it’s simple inflammation. Another recent report suggests that TRD could be caused by low levels of the two genes needed to make brain circuits. If that’s the case, this would explain why antidepressants—which increase serotonin or norepinephrine—may not work as a one-size-fits-all treatment.

It’s also common for people who once had success on an antidepressant to experience a “poop-out” effect known as tachyphylaxis. Studies estimate that 25-30 percent of those on antidepressants will experience this effect at some point. The reason? No one’s quite sure.

Who Is At Risk?

A wide range of individuals are susceptible to TRD. Unsurprisingly, it follows many of the same patterns as depression:

  • People with previous episodes of depression
  • Senior citizens
  • Women
  • People with underlying medical conditions such as chronic pain, substance abuse, and sleep disorders
  • Those with bipolar disorder or post-traumatic stress disorder

How Do You Treat Treatment-Resistant Depression?

So how do you treat depression that is, by definition, treatment-resistant? “While TRD often predicts poor response to standard antidepressant medications, a history of TRD isn’t necessarily a predictor of poor response to electroconvulsive therapy or rapid acting medications like ketamine or esketamine (Spravato),” says Krystal. To fight TRD, the medical community is embracing an array of methods—some familiar, some totally unexpected:

  • Ketamine and esketamine. Originally developed as an anesthetic (and popularized as a club drug) ketamine quickly produces an antidepressant effect by increasing the amount of neurotransmitters in the brain. It’s still used off-label as an antidepressant, but its cousin, esketamine, was approved by the FDA in 2019.
  • Botox. Is there anything Botox can’t do? A number of studies have identified the positive effects of injecting Botox into the “glabellar” frown lines between the eyes that are chronic to people with deep depression. “Getting rid of those lines seems to feed back to the brain,” says Papp.
  • Electroconvulsive therapy (ECT). Mention ECT and someone is sure to bring up One Flew Over the Cuckoo’s Nest. But it’s arguably the most effective treatment for depression, with a response rate of 80-85 percent. Patients are anaesthetised and given electric stimulation to the brain that induces brief seizures over a period of several weeks. Still, ECT is typically recommended as a last resort due to its side effects, including memory loss.
  • Microdosing. While not officially endorsed by most doctors, there’s no arguing with success. Some studies find that microdosing with psychedelics, like LSD and magic mushrooms, help depression.
  • Future antidepressants. While it’s still early days, Papp notes the promising success Sobuxun, a medication used for opiate dependency, that also seems to create an antidepressant effect. A new post-partum depression medication, given as an IV infusion over 2.5 days, has also shown incredible results that could translate to a new class of antidepressants.

How To Deal With Treatment-Resistant Depression

Part of handling TRD is finding ways to cope with the extra frustration of not being able to find a prescription that works.

  • Try talk therapy. Don’t underestimate the value of therapy, whether you like cognitive behavioral therapy, mindfulness-based cognitive therapy, or something else entirely. There’s no right answer here.
  • Find your zen. Some people are more relaxed during yoga class while others prefer a quiet journaling session. If you’re releasing stress, you’re doing it right.
  • Avoid self-medication. It’s a vicious cycle: Drinking can heighten depression. And sometimes we drink because we’re depressed. Be honest about your relationship with alcohol and drugs, and get help if needed.
  • Remember self-care. It all comes back to the basics. Eat well. Get sleep. Exercise.
  • Don’t settle. No matter how long it takes, it’s important that you find a treatment that actually works. Communicate with your doctor about what you’re feeling.

Having treatment-resistant depression can be really (really) frustrating. But, it doesn’t mean you’ll feel like this forever. There are things you can do. Keep the communication lines open with your health care pro. You’ll get through this.

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Last Updated: Mar 27, 2020