A Silent Epidemic: Treatment-Resistant Depression


By Scott Aaronson, MD

Depression can make a person hopeless: a truism. What if the sentence was lengthened? Depression can make a person hopeless, and hard-to-treat depression can make a person even more hopeless, not just because it’s a hallmark of the disease, but because of the way people with it are managed.

This longer sentence is also unfortunately true, even in the 2020s, a decade where honesty and transparency in mental health is greater than ever before. While mental health stigma may be diminishing, the pressure on mental health is increasing. Pandemic, politics, economy, loneliness, fear: Depression skyrocketed with the onset of the COVID-19 pandemic and has been on the rise.

Although complete remission of symptoms is possible, up to a third of patients do not find relief with the first or even second antidepressant prescribed to them. Depression that was not helped in this way was called “treatment-resistant depression” (TRD). The statistics are discouraging. After a patient fails two treatments, their likelihood of responding to a third drops to 25%. After four failed treatments, the likelihood of success with a fifth is probably 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 particularly difficult to treat and particularly debilitating. Other difficult-to-treat types of depression that I focus on in my work are bipolar depression and depression with suicidal ideation. These conditions are underserved, with little research-based evidence and poor outcomes. For many, antidepressants are accessible, inexpensive, and effective, but patients with conditions such as TRD often find themselves out of options.

These patients find themselves abandoned and this is not an emotional projection, it is a reality. Pharmaceutical companies have traditionally avoided it because it’s so difficult to treat.

Patients have told me how they learned that they could be denied access to a clinical trial, or even treatment, if they were candid about their multiple treatment failures or the persistence of their suicidal thoughts. One patient was told, “You don’t have depression because antidepressants don’t help you. Their stories are heartbreaking and psychiatrists need to do better to ensure their conditions are investigated and understood.

There is innovation in the form of new treatments in the pipeline. There is an increased awareness. There is hope. But until these positive changes bear fruit, it’s time to reconsider the serious and underserved types of depression, especially TRD, a lot.

Terminology reconsidered

Consider language, for starters. The phrase “treatment-resistant depression” has a way of placing blame, 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. Instead, I encourage the use of the phrase “hard-to-treat depression,” which emphasizes the need for clinicians to work harder and does not imply the futility of effort.

The goals of treatment reconsidered

Standard measures of success for garden-type depression are often extrapolated for hard-to-treat depression, and that needs to change. Remission is a problematic goal because it is often seen as an all or nothing. Meanwhile, patients tell us that what they need isn’t a low chance of perfection, but a higher chance of symptom relief. Psychiatry needs to update its dashboards based on the realities of their lives.

The Depression Monolith Reconsidered

I propose a staging of depression similar to what is done in oncology: a way of looking at a patient’s case based on a variety of factors that should influence how they are treated. For difficult-to-treat depression, this should include factors such as time since diagnosis; presence of comorbid conditions; previous experience with treatments. Ignoring these variables, as is too often the case, decreases the likelihood that a treatment strategy is likely to help.

Treatment options reconsidered

Patients are desperately looking for options. But they’re up against a medical community that’s prone to making a few missteps: first, abandoning hard-to-treat depression as a lost cause, and second, maintaining old-fashioned barriers between drug therapy and psychotherapy.

Essential readings on depression

Some of the innovations currently being explored in research work in the significant space between these two disciplines. The use of psychedelics – particularly psilocybin, which is one of the therapies I study – seems to make patients more willing to change the thought patterns that underlie depression; these treatments work as and with the therapy, not instead of it. I hope my trials, and others taking place around the world, will continue to give patients hope.

This 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 to see their patients suffer.

If there’s a silver lining to those pandemic years, maybe it’s allowed for more conversations about mental health. But my goal is that these years also produce more effective treatments. I am optimistic that new modalities are in sight.

Doctor Scott Aaronson

Source: Sheppard Pratt, with permission

Scott T. Aaronson is Assistant Professor of Psychiatry at the University of Maryland School of Medicine, Distinguished Fellow of the American Psychiatric Association, and Fellow of the American College of Psychiatrists. He also sits on the board of the American Society of Clinical Psychopharmacology. He is a psychiatrist, director of clinical research programs and scientific director of the Institute for Advanced Diagnostics and Therapeutics at Sheppard Pratt, where he is the principal investigator of several studies on the development of therapies for psychiatric disorders.


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