photo of transcranial magnetic stimulation

By Gonzalo Laje, MD, as told to Kara Mayer Robinson

I’m a psychiatrist, board certified in child, adolescent, and adult psychiatry. After my own personal experience with depression during my 20s, I’ve been on a lifelong quest to both understand and help others.

I spent almost a decade at the National Institutes of Health searching for ways to predict which depression treatments may be most effective for different people. Today, I manage Washington Behavioral Medicine Associates, a group practice in Chevy Chase, MD, where we help patients of all ages with treatment-resistant depression, or TRD.

Here’s what you should know about TRD and advances in treatment.

How do you know it’s TRD?

Most experts would agree the definition of treatment-resistant depression is the failure of two or more antidepressants, prescribed and taken at maximum dose, for at least 6 weeks each.

What can you do if you have TRD?

There are many options for successfully treating TRD. However, this doesn’t mean it’s going to be easy to find successful treatment.

My approach to TRD involves offering support from multiple angles. I don’t just focus on depression meds, but on an overall strategy that includes:

  • Dietary changes
  • Exercise
  • Medical evaluation with comprehensive bloodwork
  • Medication
  • Neuromodulation
  • Psychotherapy
  • Restorative sleep
  • Supplements and vitamins, especially if we find a deficit

First, I find out the details of previous treatments. It’s important for your doctor to understand how your symptoms evolved and how you responded to previous treatments. Your doctor may ask which medications you tried, the doses, how long you used them, and if you had side effects.

Then I look at the broader medical picture. Could there be other factors at play? Do you have good sleep habits, diet, and exercise?

I may recommend supplements, vitamins, and medication to improve day-to-day life. For example, vitamin D or omega-3s may help with mood improvement. I also address the constant negative self-talk that comes with depression.

Finally, I look for a combination of medications and neuromodulation to help your brain function in a more harmonious way.

Which treatments are best for TRD?

In the last 15 years, we’ve had a welcome introduction of different evidence-based strategies to treat TRD. They involve medication and techniques involving brain stimulation or inhibition, which is called neuromodulation.

Medication. For TRD, we go beyond classic depression medications like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

We may use medications like tricyclic antidepressants, lithium, thyroid hormone, and monoamine oxidase inhibitors (MAOIs). We may combine these with other medications, like atypical antipsychotics, buspirone, or other mood stabilizers. The combination of options is enormous.

Ketamine is an old anesthetic drug that’s been shown to help relieve TRD within hours. This is a big difference from typical depression meds, which may take weeks. There’s been some controversy around ketamine, but it offers hope for severe cases with limited options.

Neuromodulation. This is a treatment strategy that uses physical methods, like electric currents, to stimulate your brain.

One type is electroconvulsive therapy (ECT). It’s been poorly portrayed in movies and has fueled misinformation and distrust, but it’s a very safe and effective method to treat depression. ECT sends a small dose of electricity through your brain to change your brain chemistry and reverse your symptoms.

Another type is repetitive transcranial magnetic stimulation (rTMS). This is an FDA-approved treatment that delivers a magnetic pulse through a coil placed in your scalp. The pulse may stimulate or inhibit nerve cells in the part of your brain that involves mood control.

rTMS has minimal side effects and results have been positive. It’s my preferred method, and I often pair it with other treatment strategies.

What other treatments might doctors try for TRD?

Light therapy is a well-established treatment option for people whose depression may be seasonal. If your mood deteriorates in the fall months, it may have a seasonal component.

Light therapy can ease symptoms, improve sleep, and increase energy. It depends on the device, but your doctor may recommend using light panels or goggles every morning for about 20-30 minutes, starting in the fall.

Psilocybin, or “mushrooms,” has been studied as a possible depression treatment for many years. It’s not clear if it’s better than traditional antidepressants, but it may have fewer side effects. It may be an option if you’ve tried other things and they didn’t work. Talk to your doctor to see if it's a good option for you.

Nitrous oxide (N2O), commonly known as “laughing gas,” may help with depressive symptoms. It’s fast-acting and may be similar to ketamine. But there’s no clear strategy yet for how to use N20 for depression. This may change in the near future as more research is being done now.

Does psychotherapy help TRD?

Psychotherapy is an important part of your treatment strategy.

In most cases, I favor talk therapy strategies that focus on the here and now. Therapies that help you solve problems, understand why you feel stuck, promote a healthy mind-body connection, and help you recognize and handle emotions are often the most effective.

Depending on your situation, one type of therapy may be better than another. In many ways, I think of the different types of therapy through the same lens as different medications: Some work better for one kind of problem and some work better for others.

What are common challenges in treating TRD?

The first challenge is getting the right diagnosis. To find the best treatment, it’s important to understand other conditions you may have, like anxiety, obsessive-compulsive disorder, personality disorder, or other medical problems.

Since we don’t yet have very good predictors to know if we should pick one strategy over another, it’s a process of trial and error. This can be challenging and may fuel anxiety and frustration.

What can you do to improve your chances of finding a treatment that works?

Work with your primary care provider and a therapist to try different strategies. It may be helpful to consult an experienced psychiatrist or psychopharmacologist.

There are many treatment options. I’ve had many patients say, “I’ve tried them all,” “Nothing is going to help me,” or “You don’t know what it’s like.” But depression is an illness like any other. If your treatment doesn’t seem to work, it may be time to discuss other strategies with your provider.

Show Sources

Photo Credit: Philippe Garo / Science Source


Gonzalo Laje, MD, MHSc, FAPA, director, Washington Behavioral Medicine Associates.

Science Translational Medicine: "A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression."

Mayo Clinic: “Treatment-resistant depression.”