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What You Need to Know About Treatment-Resistant Depression

What You Need to Know About Treatment-Resistant Depression Depression can be effectively treated with psychotherapy and medication. But it takes time to find the correct medication and dose. Still, for about one million patients with depression, even several trials of medication don’t seem to be enough, and their symptoms linger.

These individuals may have treatment-resistant depression (TRD) or refractory depression. While there’s some debate over the precise definition, treatment-resistant depression is typically thought of as failing to achieve remission after two treatments or two antidepressants, according to George Papakostas, M.D., director of Treatment-Resistant Depression Studies in the Department of Psychiatry at Massachusetts General Hospital.

Why Some People Have Treatment-Resistant Depression

People develop treatment-resistant depression for many reasons. Some struggle with severe depression, which is difficult to treat. Medical illness and comorbid psychological disorders — such as drug or alcohol abuse or eating disorders — also complicate treatment response, according to Dr. Papakostas and Yvette Sheline, M.D., professor of psychiatry and the director for the Center for Depression Stress & Neuroimaging
 at the Washington University in St. Louis. Severe stress also can impact improvement, Dr. Sheline said.

A variety of genetic, neuroimaging and electrophysiological studies have investigated the underlying causes of treatment-resistant depression. And researchers know one thing for sure: Refractory depression is not the result of one brain region or neurotransmitter system.

Preliminary research suggests that individuals with depression may have abnormalities in the frontal and temporal regions in the brain and dysfunction in serotonin modulation. Also, the subgenual cingulate (Cg25), which is located under the cortex along the midline of the brain, may play a role. Cg25 is activated when an individual experiences sadness. It also connects to other regions involved in mood, motivation and sleep. When antidepressants are effective, this area is less active. Some researchers have hypothesized that in refractory depression, Cg25 doesn’t turn off. In general, according to Papakostas, there isn’t enough evidence to show a consistent or unifying theory.

Other individuals may not have refractory depression after all. For instance, according to Sheline, a thyroid problem may mimic depression. Individuals may have bipolar disorder — though there’s recent evidence that bipolar disorder may be overdiagnosed in patients who appear to have treatment-resistant depression — or a long-term low-grade depression called dysthymia. If a treatment isn’t working, it’s critical that your physician re-evaluate your diagnosis.

Treatment Options for Treatment-Resistant Depression

According to Sheline, there’s disagreement about the number of medication trials a person needs to try before moving onto more invasive interventions. While physicians determine this on an individual basis, it’s important for patients to have an adequate dose of medication for an adequate amount of time, Sheline said. “Each antidepressant has different therapeutic dose ranges, and these also vary according to individual factors, such as age,” she said. An adequate duration of treatment is usually six weeks. If there’s partial improvement, doctors may recommend patients stay on the medication for six to 12 weeks, Papakostas said.

This is why it’s especially important to take medication as prescribed. Many patients stop taking their medication after a week if they don’t get better, Sheline said. But this isn’t enough time to see improvement. Skipping or forgetting a dose can decrease a medication’s efficacy and make it look like it’s not the right medication for you. Also critical is practicing healthy habits, such as engaging in physical activities and getting enough sleep, and managing stress. Exercise boosts mood, while stress and lack of sleep exacerbate depression.

If one antidepressant truly doesn’t work, physicians will typically prescribe an antidepressant from a different drug class. Or they’ll prescribe an augmenting agent, such as lithium or an atypical antipsychotic medication to boost the effectiveness of the antidepressant.

If medication and psychotherapy are unsuccessful, these are other options:

Electroconvulsive therapy (ECT)

ECT involves placing electrodes on a patient’s scalp, which sends a specific current that induces a short seizure in the brain. In the 1950s, ECT developed a bad reputation because it was administered without anesthesia and with a high voltage, Sheline said. But today, it’s a completely different treatment, she said.

ECT is administered with general anesthesia and the voltage is carefully controlled. In fact, Sheline noted that there is ongoing work to decrease the pulses to minimize side effects. There’s also been concern that ECT is involuntary, Papakostas said. He clarified that ECT is voluntary and requires a patient’s informed consent.

ECT does have various bothersome side effects, including memory loss and headaches. It’s understandable why patients would hesitate to try it, Papakostas said. However, both Papakostas and Sheline agree that a large body of research substantiates ECT’s efficacy. When compared with medication and psychotherapy, ECT appears to work faster and has a higher chance of success, according to Papakostas. It also has the most efficacy data of all the more invasive interventions.

Transcranial magnetic stimulation (rTMS)

According to Papakostas, this treatment is second to ECT in quality of data. Transcranial magnetic stimulation doesn’t require anesthesia or induce a seizure like ECT. Instead it creates a magnetic field that produces an electric current in a specific area of the brain. It’s typically used for mild to moderate depression. The Food and Drug Administration has approved one device called the NeuroStar TMS to treat depression, which may be used after one antidepressant has failed.

Vagus nerve stimulation (VNS)

In 2005, the FDA approved vagus nerve stimulation for treating treatment-resistant depression. The device is surgically implanted onto the vagus nerve on the left side of the neck and delivers mild electrical impulses. Think of it as a cardiac pacemaker. According to the University of Maryland Medical Center, it sends 30-second impulses to the vagus nerve every five minutes.

For over a decade, VNS has been used to treat patients with epilepsy. Researchers began studying VNS for refractory depression when they noticed that some patients’ moods improved. Whether VNS is an effective treatment for refractory depression is unclear. It appears to help some people tremendously but not others. To date, “the data [on VNS] just isn’t on par with ECT or rTMS,” Papakostas said.

Not finding a treatment that lifts your depression can be utterly frustrating and make you feel hopeless. But while it may take more time and effort, together with your physician, you can find a treatment that works for you. Remaining optimistic is important. “Being able to maintain a positive, hopeful attitude is as critical as [getting the right treatment], Papakostas said.

Ketamine or Esketamine

Esketamine (brand name: Spravato) — a form of ketamine — was approved in March 2019 for treatment-resistant depression. The application approved by the FDA is for a nasal spray that must be administered in a doctor’s or psychiatrist’s office. While it’ll likely be less expensive than the off-label ketamine IV clinics that have popped up in recent years, it’s unlikely to be cheap. And it remains to be seen whether it will be covered by health insurance as an approved treatment.

Other Options

A small pilot study has found that neurofeedback may be an effective treatment for TRD. Because the study had a small sample size, additional research is needed to ensure neurofeedback is actually effective on a more diverse population of people who have been diagnosed with treatment-resistant depression.

What You Need to Know About Treatment-Resistant Depression

Margarita Tartakovsky, M.S.

Margarita Tartakovsky, M.S. is an Associate Editor and regular contributor at Psych Central. Her Master's degree is in clinical psychology from Texas A&M University. In addition to writing about mental disorders, she blogs regularly about body and self-image issues on her Psych Central blog, Weightless.

APA Reference
Tartakovsky, M. (2019). What You Need to Know About Treatment-Resistant Depression. Psych Central. Retrieved on August 9, 2020, from
Scientifically Reviewed
Last updated: 28 Mar 2019 (Originally: 17 May 2016)
Last reviewed: By a member of our scientific advisory board on 28 Mar 2019
Published on Psych All rights reserved.