For people with TRD, a treatment plan including antidepressant medications may not always work according to experts.

In an earlier post, we outlined what treatment resistant depression (TRD) is and the challenges it poses for those who suffer from it. While there are numerous FDA approved antidepressant medications that can help treat depression, sometimes a depressive episode is so severe that it is unresponsive to the usual antidepressant treatment options that are available. When this happens, it makes an already difficult mental illness even more difficult to treat.

What makes my depression treatment-resistant?

While there is no shortage of theories explaining why so many people do not respond to antidepressants, the cause is likely attributable to a fundamental misunderstanding of depression’s biology. Some scientists believe depression is caused by low levels of happiness-signaling chemicals like serotonin and norepinephrine. Others claim it is 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 is the case, this would explain why antidepressants—which increase serotonin or norepinephrine—may not work as a one-size-fits-all treatment. It is also common for people who once had success on an antidepressant to experience a “poop-out” effect known as tachyphylaxis. A study by the National Institute of Health estimates that 25-30 percent of those on antidepressants will experience this effect at some point.

How do you treat depression that is, by definition, treatment-resistant?

According to a recent article, John H. Krystal, MD, McNeil Professor and Chair of Psychiatry at Yale, says “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 (ECT) or rapid acting medications like ketamine or esketamine (Spravato)”. 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 is still used off-label as an antidepressant, but its cousin, esketamine, was recently approved by the FDA in 2019.
  • Botox. Is there anything Botox cannot do? Several 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 is arguably the most effective treatment options for someone with a major depressive disorder and has a response rate of 80-85 percent. Patients are anesthetized 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.
  • Transcranial Magnetic Stimulation. Transcranial magnetic stimulation (TMS) is a medical procedure that stimulates your brain with magnetic pulses. This FDA approved treatment method has been around for more than a decade and is a treatment option for those with a severe depressive disorder.
  • Vagus Nerve Stimulation. This treatment option uses electrical impulses to stimulate the vagus nerve (found in the brain). This typically requires a medical device to be surgically implanted, however, newer, noninvasive devices have been invented that do not require a device to be implanted.
  • Cognitive Behavioral Therapy. More commonly known as CBT, this is the type of treatment that you receive with a therapist (psychotherapy). Working with a therapist is widely regarded as an effective treatment method when used in conjunction with other therapies.
  • Future antidepressants. According to the National Institute of Mental Health, antidepressants are a common treatment method and new antidepressant medications are constantly being developed. In fact, 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.

The treatment of TRD is challenging and it is not easy to find ways to cope with the frustration that stems from being unable to find a treatment option that works. Remember, this does not mean you will feel like this forever – keep the communication lines open with your health care professional and you will get through this.

Boston Clinical Trials is specializing in conducting clinical trials for treatment resistant depression. Sign up here to receive more information about ongoing and upcoming paid depression studies.