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The Hushed Epidemic of Treatment-Resistant Depression

Depression can make a person hopeless: a truism. But what if the sentence were expanded? Depression can make a person hopeless, and difficult-to-treat depression can make a person feel even more hopeless—not only because that’s a feature of the condition but because of how people with it are managed.

This longer sentence is true, too, unfortunately, even in the 2020s, a decade seeing greater honesty and transparency about mental health than ever before. While mental health stigma may be lessening, mental health strain is growing. Pandemic, politics, economics, loneliness, fear: Depression skyrocketed with the onset of The covid-19 pandemic has continued to increase.

While complete remission of symptoms is possible, up to one-third of patients do not find relief from the first, or even second, antidepressant they are prescribed. Depression that has not been helped in this way has been termed “treatment-resistant depression” (TRD). The statistics are disheartening. After two treatments fail to work for a patient, their likelihood of responding to a third drop to 25 percent. After four treatments fail, the likelihood of success with a fifth is likely in the single digits. Severe TRD is the current term for patients for whom four or more antidepressants have not worked.

My research and practice focus on forms of depression like this, which are especially challenging to treat and particularly debilitating. Other types of difficult-to-treat depression I concentrate on in my work are bipolar depression and depression with suicidal ideation. These conditions are badly underserved—with little research-based evidence and poor outcomes. For many, antidepressants are accessible, inexpensive, and effective, but patients with conditions like TRD often find themselves out of options.

These patients find themselves abandoned—and that’s not an emotional projection, it’s a reality. Pharmaceutical companies have traditionally steered away because it’s so difficult to treat.

Patients have shared with me how they learned that they could be denied access to a clinical trial, or even to get care if they were forthright about their multiple treatment failures or the persistence of their suicidal thoughts. One patient was told, “You don’t have depression, because antidepressants aren’t helping you.” Their stories are heartbreaking, and psychiatrists need to do better at making sure their conditions are researched and understood.

There is innovation in the form of novel treatments in the pipeline. There is increased awareness. There is hope. But until such positive changes bear fruit, it’s time to reconsider a great deal about the severe and underserved types of depression—in particular, TRD.

Terminology Reconsidered

Consider the parlance, for starters. The phrase “treatment-resistant depression” has a way of putting the onus—if only linguistically—on patients. It’s not that patients are stubborn or recalcitrant—it’s that the system is failing them with a lack of effective treatment options. I encourage the use of the phrase “difficult-to-treat depression” instead, which puts the emphasis on the need for clinicians to work harder and does not connote futility for the effort.

Treatment Goals Reconsidered

The standard measurements of success for garden-variety depression are often extrapolated for difficult-to-treat depression, and that needs to change. Remission is a problematic goal because it’s often seen as an all-or-nothing.

Meanwhile, patients tell us that what they need are not low odds at perfection but higher chances of symptom alleviation. Psychiatry needs to update its scorecards to the realities of their lives.

The Monolith of Depression Reconsidered

I propose a staging of depression similar to what is done in oncology: a way of considering a patient’s case based on a variety of factors that should influence how it’s treated. For difficult-to-treat depression, that should include factors like the length of time since diagnosis; the presence of comorbid conditions; prior experience with treatments. Ignoring these variables—as is the case too often—lessens the likelihood that a treatment strategy is likely to help.

Options for Treatment Reconsidered

Patients are desperate for options. But they’re facing a medical community that is prone to making a couple of missteps: first, giving up on difficult-to-treat depression as a lost cause, and, second, keeping old-fashioned barriers up between pharmacotherapy and psychotherapy.

Some of the innovations currently being explored in research work are in the important space between these two disciplines. The use of psychedelics—in particular, psilocybin, which is among the therapies I’m investigating—seems to make patients more amenable to changing the thought patterns that underlie depression; these treatments work as, and with, therapy, not instead of it. I’m hopeful that my trials, and others taking place around the world, will continue to give hope to patients.

That sense of hope is why this has been my field of study for 40 years—and continues to be. I’m here because there are still too many patients who feel they have nowhere to turn and too many clinicians who are frustrated watching patients suffer.

If there’s any silver lining to these pandemic years, it may be that it’s enabled more conversations about mental health. But it’s my goal that these years also yield more effective treatments. I am optimistic that novel modalities are in sight.

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