Treatment-Resistant Depression

Sometimes treatment-resistant depression is the reason why you don’t seem to get better. Here are a few things that may cause it, other treatments you can benefit from and how to cope.

What Treatment-Resistant Depression Is

coping with treatment resistant depression
Photo by Anh Nguyen

Treatment-resistant depression (TRD) is one of the worst things that might happen to anyone suffering from a major depressive disorder. Treatment-resistant depression is described as depression that has failed to respond to at least two different antidepressant treatments. If anyone who has experienced depression can describe how inescapable and hopeless it can feel, this condition would be totally hopelessly indescribable. Imagine how devastating it will be for one who is already suffering enough from depression to be told it will be difficult to find a treatment.

Fairly Common Problem

If you fall into this category of patients, do not panic because you are not alone. 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 the standard antidepressants.

Causes Of 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 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.

Those 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

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. For example if you haven’t had an adequate response to antidepressant medication by about 10 weeks of treatment with the optimal dose.

Specifically watch out for these signs

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

How To Be Sure It’s Treatment-Resistant Depression

TRD is easy to misdiagnose for a number of reasons. Sometimes also doctors can 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. 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.
  • Conflicting medications. Even then, there are other reasons antidepressants might not work correctly. As with some other conditions when some other medications you might be on reduces the efficacy or interferes with its action of your prescribed drugs, some medications—like blood pressure, antibiotics, or steroids—can speed up the enzymes that metabolize antidepressants too quickly.
  • Other health issues. 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.

Treatments You Can Benefit From

So what might work if you have been diagnosed with treatment-resistant depression? Although with TRD you might react poorly to standard antidepressant medications, there are other treatments that can still work for you like electroconvulsive therapy or rapid acting medications like ketamine or esketamine.

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.

Electroconvulsive therapy (ECT)

The talk of ECT makes some shiver but the truth is that it works. It is 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.


 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.

Coping With Treatment-Resistant Depression

While part of handling TRD is finding ways to cope with the extra frustration of not being able to find a prescription that works,there are a few things that can help you cope better.

  • 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.
  • Do not self medicate. It’s a vicious cycle: Drinking can heighten depression. It is true that 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 give up. 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.

Always Remember

Having treatment-resistant depression can be really (really) frustrating. But, it doesn’t mean you’ll be like this forever. Keep the communication lines open with your health care pro. Do not give up. Yes it might take a long while but you will get through this.

Article Sources 

  • A third of symptoms don’t get better: Dialogues In Clinical Neuroscience (2015). “Pharmacological approaches to the challenge of treatment-resistant depression.”
  • Is there a genetic component?: The International Journal Of Neuropsychopharmacology (2019). “The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives.”
  • Sometimes antidepressants just stop working: Innovations In Clinical Neuroscience (2014). “Identification And Treatment Of Antidepressant Tachyphylaxis.”
  •  Seniors and risk: Journal Of Psychiatry & Neuroscience (2015). “Treatment-Resistant Depression In Later Life.”
  • Women and TRD: PLOS ONE (2013). “Characterization of Treatment Resistant Depression Episodes in a Cohort of Patients from a US Commercial Claims Database.”
  • More about microdosing: Psychopharmacology (Berl)  (2019). “Microdosing Psychedelics: Personality, Mental Health, And Creativity Differences In Microdosers.”

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