Difficult-to-Treat Depression: A New Approach to Treatment-Resistant Depression
Scott T. Aaronson, M.D.

Dr. Aaronson is Director of Clinical Research and a psychiatrist at the Retreat at Sheppard Pratt Health System and a clinical associate professor of psychiatry at the University of Maryland School of Medicine.

In 2018, Dr. Aaronson and colleagues published an article* proposing a reframing of depression treatment and discontinuing use of the term “treatment-resistant depression.” Here, he provides an overview.

How would you describe the current approach to depression treatment?

Currently, treatment is viewed as three phases: acute, continuation, and maintenance. Acute treatment is meant to bring the person with depression into remission, with their depression symptoms alleviated. Continuation treatment is meant to prevent relapse into the just-treated depression. Maintenance treatment is meant to prevent a recurrent (new) depression episode.

This three-phase approach has limitations. I am especially struck by the disconnect between the treatment goal of full remission and the reality that many people cannot achieve, or sustain, that remission. For some people, a focus on functioning and controlling symptoms may be more appropriate. We need to acknowledge that not everyone will get fully well.

In addition, there’s not good evidence to support the sequence of treatments, whether individually or in combination. Researchers have not fully explored the range of treatments available, particularly neurostimulation interventions, in the progression of treatment.

What are the problems with our current understanding of treatment-resistant depression?

The main problem is that it lumps all patients who have not been effectively treated by a certain number of medication trials into one group. We know that the brain involves both chemical and electrical processes, so it is not necessarily accurate that someone is “treatment resistant” if they have only tried medications. We also don’t distinguish between people who have not responded from people who have not been able to maintain their response (i.e., relapse). Not all depressions are the same, so why do we call them all the same and think they should be treated in the same way?

What is your proposal to reconceptualize treatment-resistant depression?

The current three-phase structure of depression treatment presumes that people will achieve remission and be able to sustain it, similar to treatment for cancer. Unlike cancer treatment, however, people with depression don’t necessarily become free of the condition or all of its symptoms. In one study, only about 1 in 10 patients with depression in remission were entirely symptom-free after two courses of treatment.

Instead, for a good number of people living with depression, it makes sense to take our cues from the field of cardiology. With chronic heart disease, “full recovery” is not feasible, so treatment is oriented to support the person in achieving their best health and best quality of life despite their heart condition. The treatment goals are to reduce the impact of symptoms and side effects on the person’s life and to encourage behaviors that support good heart health, such as quitting smoking, losing weight if appropriate, exercising, following a balanced diet, and managing stress. In other words, cardiac patients aim to manage their heart disease in a way that controls symptoms and supports daily functions and a good quality of life.

With depression, when treatment to date indicates that becoming symptom-free is not likely, it makes sense to aim treatment toward managing the depression, its symptoms, and the treatment side effects in a way that affords the best level of function and mental wellness under the circumstances.

Practically speaking, what is the difference for people living with depression?

We need to change how we think of what constitutes a meaningful outcome of treatment. Having people return to their pre-depressive episode lives without significant negative side effects, functioning as well as they did then, is generally the goal of depression treatment. But we know that this goal is realistically not achievable for everyone.

Just as people who experience a cardiac event cannot reasonably expect to have their heart be the same as it was before the heart attack, clinicians, people living with depression, and families must align their expectations to the reality that people living with depression are not always able to regain their full functioning, despite otherwise effective treatment that alleviates some but not all symptoms. For some, managing the depression with all available interventions, trying appropriate new treatments as they become available, and developing strategies to cope with remaining symptoms (generally through psychotherapy) may be the best outcomes they are able to achieve. Though short of the ideal outcome, using the difficult-to-treat model can be enough to support people in reclaiming their work lives, overcoming suicidal ideation, and being able to engage as parents and partners.

I believe that this approach has a psychological benefit. I am sure that some people may consider this aiming too low for defining successful treatment. However, for people who have unrelenting depression, the implicit (if not explicit) pressure to achieve nonrealistic goals can add to their sense of worthlessness and despair, thus exacerbating their depression. We should accept that acknowledging their progress and maintaining those gains – even if not a return to full functioning, but reflective of their personal values – is, for some, the very best that they can do.

How does this approach to unremitting depression affect families and their role in supporting their loved one?

I believe it is a positive change. Chasing unattainable goals creates unnecessary stress and depletes resources, including the capacity of caregivers. Setting – and achieving – more realistic treatment goals can restore a level of predictability to their lives as expectations align better with the person’s abilities. Being a caregiver to a person with ongoing depression presents a variety of challenges, including physical, emotional, logistical, interpersonal, and more. Using the difficult-to-treat framework facilitates the re-imagining of relationships, re-distribution of responsibilities, and reconciliation with their new reality. It also allows for celebration of being “well enough” to work on rebuilding their lives.


* Rush, A.J., Aaronson, S.T., and Demyttenaere, K., “Difficult-to-treat depression: A clinical and research roadmap for when remission is elusive,” Aus & NZ J. Psychiatry 53:2, pp. 109-118 (Online Oct. 31, 2018; print Feb. 1, 2019).

Read an overview of Treatment-Resistant Depression

Read one family’s account, in Ronnie’s story