Depression 10 Sep, 2025 Read Time: 5 mins

State-of-the-art in treatment resistant depression

Treatment-resistant depression (TRD) has been variably described as depression that has failed to remit symptomatically despite at least one or two consecutive antidepressant (ADT) treatment trials at a therapeutic dose and of adequate duration.1,2 However, there is no consensus definition or universal framework for TRD, which has implications clinically, especially when it comes to accurately describing its prevalence and informing policy.1 Dr. Roger McIntyre, Professor in the Departments of Psychiatry and Pharmacology at the University of Toronto, discussed the state-of-the-art on diagnosis, terminology, and management of TRD during a virtual educational webinar called “Improving the Lives of Patients with Depression” offered by the Neuroscience Education Institute (NEI).

Prevalence and burden of TRD

Major depressive disorder (MDD) is both a disabling illness, with depressed individuals in Canada having a substantially lower health-adjusted life expectancy and higher rate of premature mortality compared to non-depressed individuals.3 TRD disproportionately contributes to the overall economic burden of MDD, with nearly half of the annual economic burden of medication-treated MDD being attributable to TRD.4 This may not be surprising given that only one in three patients with MDD achieves remission using their first ADT, and two in three patients require four different ADT trials before achieving symptom remission.5 Importantly, each subsequent ADT trial has a lower likelihood of achieving symptom remission and it takes longer to achieve.5 Moreover, the association between symptom remission and functional recovery is nonlinear at later stages of the disease journey, at which point functioning is less likely to return to baseline–even if a patient remits symptomatically.6 Dr. McIntyre explained that this disconnect between symptom remission and functional recovery could be due in part to changes in the disease over time. Specifically, persistent symptoms of cognitive dysfunction, anhedonia, lack of motivation, and fatigue can make it more difficult for patients to function better.

Two-thirds of patients with MDD fail to achieve symptom remission on an initial antidepressant5

Problems with current definitions of TRD

TRD classification varies by the number of previous ADT treatment failures. Many regulators define a threshold of at least two consecutive ADTs, but some research groups have a lower threshold of one ADT failure.1 According to Dr. McIntyre, current definitions and criteria for TRD are incomplete and many important parts of the story are missing. For example, they do not distinguish between failures of different classes of ADTs, psychotherapy, neurostimulation therapies, or different types of adjunct or combination therapies; they do not reflect baseline disease severity, psychosocial impairment, episode duration, or different features such as anxiety, anhedonia, mixed features, or history of childhood adversity; ‘failure’ is not clearly defined and does not account for partial response or residual symptoms; and they fail to consider patient-reported outcomes, which tend to be more focused on quality of life and functioning than on depressive symptoms.1,2,7 Notably, current definitions for TRD do not accurately reflect the clinical presentation of ‘difficult-to-treat’ (DTD) depression, a concept that is gaining more traction. Indeed, the recently updated 2023 Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of MDD distinguish between TRD and DTD, with the latter being a broader definition (i.e. including psychotherapy, neuromodulation therapies etc.) without the negative connotation of TRD2 (i.e., it does not ‘blame the patient’ for not responding to treatment). 

‘Difficult-to-treat’ depression is an emerging concept that is more descriptive and collaborative than TRD1,2,7

Treatment patterns and guidelines for TRD

Despite the high prevalence and burden of TRD, evidence suggests that many patients languish on suboptimal therapy for years. In a real-world study of nearly half a million patients with MDD, the majority (91%) received monotherapy with an ADT and only 9% received an adjunctive agent. Discontinuation rates were ~80%, suggesting ineffectiveness of ADT monotherapy regimens.8 Additionally, those who received adjunctive agents generally received it as their third line of therapy more than a year after their initial ADT.8 This is in stark contrast to contemporary recommendations, including the CANMAT 2023 MDD guidelines, which advocate for earlier use of adjunctive therapy after an inadequate response to the first ADT (at an adequate dose and duration)2 and not cycling through multiple rounds of ADTs.

There is a gap in the implementation of adjunctive therapies for the treatment of TRD

Dr. McIntyre also highlighted the importance of appropriately stopping therapies when they are ineffective, in a timely manner. He cited the common clinical situation where patients with TRD undergo incremental dose increases that culminate in doses of ADTs that sometimes greatly exceed label recommendations. While dose optimization to a therapeutic level is a recommended first step when there is a limited response to an initial ADT,2 responses plateau once a therapeutic dose is reached, and additional dose increases have diminishing returns with respect to efficacy but a higher propensity for side effects.2 

When it comes to choosing the next step when there is an inadequate response after dose optimization, guidelines recommend:

  1. switching to another ADT when there are troublesome side effects or a 20% improvement from baseline in response using a validated symptom rating scale, or
  2. adding an adjunctive agent when the initial ADT is well tolerated and a partial response to the initial ADT is seen (≥20% improvement).2

The latter strategy has greater evidence for efficacy and shorter time to remission compared to switching.2 

Adjunctive strategies can target specific residual symptoms from the initial antidepressant2

Several other pharmacologic and nonpharmacologic strategies can be considered for patients with TRD or DTD. There is growing interest in, and evidence for, glutamate modulators, which are recommended as 2nd- or 3rd-line therapies by the CANMAT guidelines for DTD depending on the specific agent and route of administration.2 There are also several other investigational molecules for TRD, but there is insufficient evidence at this stage to recommend them in the routine clinical setting.1 Nonpharmacologic strategies should also be considered for TRD patients who are inadequately responding to one or more pharmacologic treatment trials.1,2 Among these, neurostimulation therapies have been shown to be highly effective in TRD, and there is evidence to support the benefits of adjunctive psychotherapies.1,2

Several evidence-based pharmacologic and nonpharmacologic strategies are recommended for TRD1,2

Despite the disproportionate burden of TRD, this remains an ill-defined concept and a heterogeneous patient population that tends to be under-represented in research trials.1 Dr. McIntyre advocated for the advancement of innovative pharmacological, psychological and neurostimulation therapies to improve outcomes in this patient population with high unmet needs.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References

  1. McIntyre RS et al. World Psychiatry 2023;22 :3.
  2. Lam RW et al. Can J Psychiatry 2024;69(9):641-687.
  3. Steensma C et al. Health Promot Chronic Dis Prev Can 2016;36 :205-13.
  4. Zhdanava M et al. J Clin Psychiatry 2021;82 :20m13699.
  5. Rush AJ et al. Am J Psychiatry 2006;163 :1905-17.
  6. Yang H et al. Frontiers Psychiatry 2022;13 :915689.
  7. Rush AJ et al. Austr N Z J Psychiatry 2019;53:109-18.
  8. Jain R et al. Drugs Real World Outcomes 2022;9 :477-86.