Treatment Resistant Depression (TRD) OR Difficult-to-Treat Depression (DTD)?

by JE

“Treatment Resistant Depression (TRD)” is a term that has been used for several decades. In the last couple of years, a new but related term has arisen: “Difficult-to-Treat Depression (DTD)”. They are both terminologies used in the medical field of psychiatry. Are they the same thing? Well essentially “yes”; but the new term DTD may have several advantages over TRD. For example, there is more optimism associated with the phrase “difficult-to-treat” compared with “treatment resistant”. For patients being told they have TRD there is a risk that they lose all sense of hope for a recovery in any form. This is especially so after they have tried several antidepressants, psychotherapy and possibly electroconvulsive therapy. DTD has advantages in that “difficult” is not the same as “impossible”. New psychotherapies, medication and neurostimulatory and neuromodulatory treatments may be available that might benefit depression that is resistant/difficult to treat.

So, what is TRD? Patients whose depressive disorder does not respond to two adequate trials of different antidepressants are said to have TRD. However, the definition of TRD is complex. What constitutes an “adequate treatment trial”? How long should the trial be for? What dose should be used? Do the antidepressants need to work differently to count? There is no clear consensus on how to determine what dose is adequate, what duration is adequate, or whether the medications need to be very different from one another or not. Even the conventional definition that TRD refers to two failed trials is not always agreed upon. For example, Gaynes proposed four TRD categories distinguished by the number of failed antidepressant treatment attempts. For patients with Major Depressive Disorder, he proposed different categories for 1 or more, 2 or more, and 3 or more treatment failures with antidepressant medication (Gaynes et al., 2020). The other for which there is no consensus is whether treatments other than medication, such as psychotherapies and neurostimulatory treatments (such as ECT or transcranial magnetic stimulation - TMS) should be counted when defining TRD, and if so, how an adequate trial of such treatments should be defined.

Aside from how TRD is defined, another concern about this term and concept is what it implies about how a person’s depression should be managed. The idea behind TRD is that episodes of depression are relatively short in duration and once treated the person is fully well, and that if a couple of treatments have not worked, then it is simply a case of trying further treatment after further treatment until the depression responds. The focus is entirely on getting rid of depressive symptoms.

However, unfortunately the situation is more complex than this. There are more reasons why it might be difficult to treat a person’s depression than simply it not responding to a short course of antidepressant. For example, sometimes depression might respond to a course of antidepressants for a period of time, but then the depression returns. The problem in this situation is helping the person remain well. Alternatively, rather than a depression not responding to medication, the problem is that the medication, or other treatments, cause intolerable side effects and so can’t be continued. Whether the problem is that the depression doesn’t respond to medication, response is not maintained, or treatment is not tolerable, the person ends up continuing to suffer from depression.

Rush and colleagues have argued that if a person’s depression is proving difficult to treat, for whatever reason, it is important to stop and consider why this might be the case (Rush et al. 2019). There are many different factors that have been shown to influence whether depression is easier or harder to treat, including:

The problems with the definition of TRD, but more importantly the negative and stigmatising nature of the term and the limited perspective that the solution is simply to try medication after medication, have led psychiatrists to propose the concept of “Difficult to Treat Depression (DTD)” (Rush et al., 2019). The idea is that if a person’s depression is proving difficult to treat, for whatever reason, this should be addressed by assessing the causes of persistent depression and then considering how best to optimise treatment, using all types available (self-help, psychotherapy, medication and neurostimulation) as appropriate, not just to control symptoms but also help improve ability to function on a daily basis and quality of life.

Unfortunately, there are many people who have DTD. Typically, they have had their first depressive episode before 30 years of age. They have had more chronic and frequent episodes and have a higher likelihood of family history of depression and more residual symptoms when better i.e. some symptoms remain (Rush et al., 2012).

The course of patient’s depression is characterised by:

  • Chronicity – i.e., lasting over long periods – years.
  • Use of many antidepressants
  • Poor functioning
  • Poor quality of life
  • High suicide rates or thoughts of suicide
  • High level of psychiatric and other medical disorders (co-morbidities)
  • High utilisation of mental health services
  • A poor acute response to treatment and increased risk of relapse despite ongoing treatment.

DTD is a broader more empathic term than TRD. DTD recognises depression as “difficult” but not “impossible” to treat (as is implied by TRD). TRD lacks empathy and suggests a defeatist attitude to treatment. A group of psychiatrists from around the world came together to agree on a definition of DTD as “Depression that continues to cause significant burden despite usual treatment efforts. The goal of the treatment shifts from remission to optimal symptom control and increasing quality of life.” (McAllister-Williams et al., 2020). A significant burden is a term that varies for individual patients. Generally, it involves an impairment in daily functioning or quality of life where the symptoms of the depression are the driver of the burden. Adverse effects of treatment can also be a burden to the patient.

These psychiatrists from around the world have also put forward recommendations as to how best to treat DTD (McAllister-Williams et al. 2020).

The first goal of managing DTD is reducing depressive symptoms as much as possible and ideally helping the person to be symptom free if possible. However, if this is not possible, at least to start with, then it is important to help patients with DTD to learn how best to cope with their symptoms to live a “meaningful” life despite having residual depressive symptoms. Patients rank having a meaningful life very highly, despite symptoms or functional limitations (Demyttenaere et al., 2015).

Patients with DTD often feel hopeless, helpless, worthless, and isolated. Therapy may help alleviate these symptoms and increase self-esteem. DTD requires an understanding what a clinically meaning benefit of treatment entails. In some cases, a 25% reduction in symptoms may reduce suicidal thoughts, allow a patient to live independently or even get employment. THE MAJOR AIM OF TREATMENT FOR DTD IS TO IMPROVE QUALITY OF LIFE.

Treatment decision making should include the patient’s opinions as well as the clinicians and should consider all treatment options: pharmacology, psychotherapy, neurostimulation and neuromodulation- with the aim of optimising the outcomes when sustained remission is unlikely.

Overall, the goal is to:

  • Strive for optimal symptom control
  • Reduce risk of impact and relapse
  • Optimise psychosocial functioning and return to a meaningful life

DTD involves the clinician and patient discussing and sharing the decision making. It supports self-management strategies and empowers patients- a key feature to long term management of DTD. DTD requires frequent reassessment and consideration of treatment direction.


TRD is likely to remain of relevance for drug approval and commissioning of services and so this term will continue to be used. However, it is hoped that psychiatrists will start to use the more optimistic sounding term Difficult-to treat-Depression (DTD) for patients whose depression has not responded to conventional or alternative treatments currently licenced to treat depression. The optimism lies in the fact that science is always advancing, and treatment should not be thought of as impossible. The aim of treating DTD is to consider all currently available treatments and where possible to eliminate depression; but at the very least help the patient to learn how to manage it and have a life they think is worth living.

For more information on DTD click here.


DEMYTTENAERE, K., DONNEAU, A. F., ALBERT, A., ANSSEAU, M., CONSTANT, E. & VAN HEERINGEN, K. 2015. What is important in being cured from depression? Discordance between physicians and patients (1). J Affect Disord, 174, 390-6.

GAYNES, B. N., LUX, L., GARTLEHNER, G., ASHER, G., FORMAN-HOFFMAN, V., GREEN, J., BOLAND, E., WEBER, R. P., RANDOLPH, C., BANN, C., COKER-SCHWIMMER, E., VISWANATHAN, M. & LOHR, K. N. 2020. Defining treatment-resistant depression. Depress Anxiety, 37, 134-145.

MCALLISTER-WILLIAMS, R. H., ARANGO, C., BLIER, P., DEMYTTENAERE, K., FALKAI, P., GORWOOD, P., HOPWOOD, M., JAVED, A., KASPER, S., MALHI, G. S., SOARES, J. C., VIETA, E., YOUNG, A. H., PAPADOPOULOS, A. & RUSH, A. J. 2020. The identification, assessment and management of difficult-to-treat depression: An international consensus statement. J Affect Disord, 267, 264-282.

RUSH, A. J., AARONSON, S. T. & DEMYTTENAERE, K. 2019. Difficult-to-treat depression: A clinical and research roadmap for when remission is elusive. Aust N Z J Psychiatry, 53, 109-118.

RUSH, A. J., WISNIEWSKI, S. R., ZISOOK, S., FAVA, M., SUNG, S. C., HALEY, C. L., CHAN, H. N., GILMER, W. S., WARDEN, D., NIERENBERG, A. A., BALASUBRAMANI, G. K., GAYNES, B. N., TRIVEDI, M. H. & HOLLON, S. D. 2012. Is prior course of illness relevant to acute or longer-term outcomes in depressed out-patients? A STAR*D report. Psychol Med, 42, 1131-49.