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4 things we now know about treatment-resistant depression

Imagine being depressed and trying medication after medication—only to find none work. That’s the plight of people with treatment-resistant depression. We look at this little-understood condition, and how researchers are working to crack its code.

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For many people coping with major depressive disorder—which includes different types of depression that persist for at least two weeks—antidepressants can play an invaluable role in helping relieve symptoms, enabling them to resume the life they once enjoyed. But for those who experience a form known as treatment-resistant depression (TRD), standard medications tend to provide little to no relief.

The disorder isn’t rare: Up to one-third of adults with major depression battle symptoms—such as persistent feelings of sadness, sleep disturbances, low energy and thoughts of death or suicide—that don’t respond to treatment.

“Although there is some disagreement as to how to define treatment-resistant depression, a patient is generally considered to have it if the individual hasn’t responded to adequate doses of two different antidepressants taken for a sufficient duration of time, which is usually six weeks,” explains Jaskaran Singh, M.D., Senior Director of Neuroscience, Janssen Pharmaceuticals, part of the Johnson & Johnson family of companies.

While there’s still much to learn, several recent and promising advances are shedding new light on how to understand and manage TRD. Recently, for Mental Health Month, we highlighted some of the most important findings—and why there may be new hope for people who’ve been living with the disorder for far too long.


Your age, gender and health status may increase your risk for treatment-resistant depression.

There’s no way to predict for sure who with depression will be unresponsive to treatment, but researchers have observed that certain populations are more vulnerable than others. Women and senior citizens, for example, seem to experience TRD at higher rates, for reasons that are likely both biological and psychological. Individuals who endure severe or frequently recurring bouts of depression also appear to be more susceptible.

A depressed person’s overall health can also play a role.

“Patients with depression who have some medical illnesses—such as thyroid disease and chronic pain—are at greater risk for TRD,” says Alexander Papp, M.D., a psychiatrist at UC San Diego Health.

Other conditions associated with TRD include substance abuse and eating and sleep disorders, which have the potential to make you more prone to being resistant to treatment with antidepressants.


Depression may have causes we don’t yet understand—which may be why antidepressants don’t work for everyone.

I saw many patients with treatment-resistant depression who told me that friends and family members believed they preferred being depressed, or weren’t trying hard enough to improve, because their antidepressants weren’t working. This isn’t about a lack of motivation.
Jaskaran Singh, M.D.

While the biology of depression is still largely a mystery, the most popular theory is that it’s caused by low brain levels of such neurotransmitters as serotonin and norepinephrine, which are associated with feelings of happiness and well-being. But recent research suggests that these neurotransmitters may not be the lone culprit—so antidepressants, which work to increase serotonin or norepinephrine levels, may not be a one-size-fits-all treatment.

“One of the more modern theories is that depression creates inflammation in the brain, or that inflammation in the brain creates depression,” Dr. Papp says. “Traditional antidepressants only affect neurotransmitters, so this may be why some patients don’t respond to them.”

Whether or not this turns out to be true, what we do know is there’s still no guaranteed fix for the problem—which can be frustrating for both patients and their loved ones.

“When I had a clinical practice, I saw many patients with treatment-resistant depression who told me that friends and family members believed they preferred being depressed, or weren’t trying hard enough to improve, because their antidepressants weren’t working,” Dr. Singh says. “This isn’t about a lack of motivation. I’ve never met a patient who didn’t want to get better.”


There are established methods for managing treatment-resistant depression.

While the words “treatment-resistant” might seem synonymous with “no hope,” the reality is that tools do currently exist to help people with TRD. A 2012 study published in the journal Patient Preference and Adherence identified five main treatment strategies—optimization, switching, combination, augmentation and somatic therapies—that psychiatrists can use to create a personalized plan for patients.

Optimization, for instance, means that “some people with TRD may benefit simply from giving their antidepressant more time to work or by taking a larger dose,” Dr. Papp says.

For others, switching to a different class of antidepressant—or adding one to the current treatment for a combined approach—may lead to remission. And augmentation may involve using medications that were developed for other uses, but that have since been approved for the treatment of TRD.

Transcranial magnetic stimulation can be an effective nondrug treatment for treatment-resistant depression

Transcranial magnetic stimulation can be an effective nondrug treatment for TRD

There are also somatic (nondrug) therapies, including transcranial magnetic stimulation—which targets nerve cells in the region of the brain involved in mood control and depression—and electroconvulsive therapy (ECT), which induces changes in brain chemistry to help reverse symptoms of TRD.

ECT—which people often refer to mistakenly as “electroshock therapy”—“is very stigmatized, largely due to how it was portrayed in the movie One Flew Over the Cuckoo’s Nest,” Dr. Singh says. But the procedure is much safer and more tolerable today, he notes, and often reserved for people with severe, drug-resistant depression. “It’s not for everyone, but it may be effective in 70 to 80% of patients,” he adds.


There’s new research being conducted on treatment-resistant depression.

Scientists at Janssen, for instance, are currently conducting clinical trials of a compound that could potentially help people with TRD by acting on different pathways in the brain than antidepressants do.

“That’s the goal at Janssen,” Dr. Singh says, “to develop new innovations that can truly impact patients by addressing an unmet need.”

What It’s Really Like to Have TRD

One woman shares her experience of living with treatment-resistant depression since college.

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