The STAR*D study, sponsored by the National Institute of Mental Health (NIMH), investigated the efficacy of treatments for major depressive disorder in individuals unresponsive to initial antidepressant therapy. It was found that approximately 50% of participants (aged 18–75 years) responded to an initial antidepressant regimen, while only 30% achieved symptomatic remission. Some showed a positive response to secondary antidepressant therapies or a combination of two medications, yet others remained unresponsive to any treatment regimen for a duration of at least 12 months. A third of the cohort failed to achieve full recovery even after multiple pharmacological interventions, demonstrating resistance to pharmacotherapy [Reference Rush, Fava, Wisniewski, Lavori, Trivedi and Sackeim1].

Treatment resistance in depression poses a significant challenge for clinicians and researchers dealing with patients suffering from depression, particularly in difficult-to-treat depression (DTD), where a clinical condition of depression is identified, which, despite standard therapeutic efforts, does not demonstrate full symptom control. This places a substantial burden on the patient, their family, and the clinical practitioners involved in their care [Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood2]. This condition significantly impacts patients’ quality of life, elevating the risk of disability, suicide, and other complications [Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood2]. DTD should not be confused with treatment-resistant depression (TRD), which has long captured the attention of the medical and scientific community. TRD does not represent a new diagnostic category but rather a clinical scenario invoked when a patient fails to respond adequately to two or more antidepressant treatments at appropriate dosages administered consecutively over a sufficient period without achieving acceptable therapeutic effects, as recently highlighted by the European Medicines Agency [3]. Over the years, TRD has been the subject of numerous classifications and research efforts aimed at identifying new pharmacological therapeutic strategies for resistant patients. The very definition of TRD has been a topic of debate among experts, as there is no shared consensus on the criteria that determine treatment nonresponse [Reference Brown, Rittenbach, Cheung, McKean, MacMaster and Clement4]. Historically, terms such as TRD and DTD have been used interchangeably and synonymously, causing considerable confusion in the scientific literature. These two clinical conditions represent distinct forms of depressive disorders that should be clearly recognized and differentiated [Reference Paganin, Signorini and Sciarretta5, Reference Zimmerman and Mackin6]. Already, 20 years ago at a symposium titled “Difficult-to-Treat Depression,” the idea was proposed that DTD was a more accurate label than TRD [Reference Kupfer and Charney7].

Recent developments and research have led to a broader and more inclusive approach to DTD, emphasizing the need to consider a concept that goes beyond mere resistance to pharmacological treatments. This new perspective, encompassing psychosocial, biological, and interactive aspects, paves the way for an integrative model of therapeutic management of resistance in depression [Reference Paganin, Signorini and Sciarretta5]. DTD is not a binary condition, but rather exists along a therapeutic response continuum. This spectrum encompasses complete responses, partial responses, and even nonresponses, shifting the treatment focus from a curative/remissive model to a disease management model that emphasizes enhancing functionality and quality of life, aiming for optimal symptom control [Reference Rush, Sackeim, Conway, Bunker, Hollon and Demyttenaere8, Reference Rush, Aaronson and Demyttenaere9]. An international consensus, comprising 15 academics from across Europe, the United States, Canada, and Australia, with expertise in affective disorders, was established in 2020 [Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood2] and has proposes a cultural and scientific shift to guide clinicians and researchers, expanding the TRD model [Reference Demyttenaere and Van Duppen10]. While TRD is associated with the inefficacy of standard pharmacological treatments, DTD encompasses a broader clinical perspective that incorporates psychological, social, environmental, and patient care system interactions that can influence treatment response. To identify patients with DTD, it is essential to consider the course of depression, symptom variability, notably the presence of anhedonia and anxiety, functional impairment, coexisting psychiatric or general medical conditions, including substance use disorders, and considerations of concurrent medications. The patient’s medical history should highlight the number and sequence of treatments undertaken, types and counts of therapeutic failures, familial history, treatment adherence, and the presence of childhood traumas [Reference Rush, Sackeim, Conway, Bunker, Hollon and Demyttenaere8]. Thus, the key distinctions between TRD and DTD pertain to the very definition of the clinical condition and the therapeutic approach. The definition of DTD represents a significant cultural shift, grounded in both clinical practice and treatment, underscoring the complexity of the condition and the importance of considering multiple variables at play [Reference Paganin, Signorini and Sciarretta5, Reference Demyttenaere and Van Duppen10].

Theorizing the DTD model’s study, it is crucial to emphasize the importance of altering the methodological approach from what was used previously. Such changes should encompass the integration of diverse operational criteria, which factor in the consensus among various experts in the research group. It is also vital to incorporate individuals who have personally experienced depression, termed as people with lived depression (PWLD), into this group. Moreover, there is a pressing need to set clear and unequivocal operational standards to pinpoint crucial elements that demand explicit definitions. These elements encompass the count of antidepressant treatments, inclusion/exclusion guidelines, validation of relevant psychometric and assessment tools, traits of pharmacotherapy, outcomes, and the assessment of the efficacy of novel therapies [Reference Zimmerman and Mackin6]. As far as DTD is concerned, it is desirable to be able to deepen the recognition of potential biomarkers and evaluate the neurobiological facets linked to the various clinical manifestations of DTD [Reference Suneson, Grudet, Ventorp, Malm, Asp and Westrin11]. Summarizing the 2020 international consensus on DTD management, the main focus should be on addressing depressive symptoms while equipping patients with coping tools. The goal of treatment requires a multidisciplinary approach that goes beyond the simple evaluation of pharmacological treatments and should move from aiming solely at remission, improvement of symptom control and quality of life [Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood2], see Table 1.

Table 1.

This approach should encompass psychotherapies, neurostimulation techniques, social and occupational interventions, all aimed at enhancing adherence and therapeutic effectiveness. It also focuses on fostering self-management of symptoms and fostering integration among healthcare professionals, patients, families, and the broader community [Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood2].

Another focus should include enhancing individual, family, professional, and social interactions, with an emphasis on harmonizing the therapeutic intentions of clinician and patient. Decisions in treatment ought to consistently integrate patient viewpoints, aligning with the expertise of medical professionals and adapting interventions to address the specific challenges presented by DTD [Reference Dodd, Bauer, Carvalho, Eyre, Fava and Kasper12]. It is imperative to scrutinize all potential therapeutic avenues, particularly, when the achievement of symptomatic remission remains ambiguous. Family involvement is of paramount importance in the treatment of complicated and difficult depressions as evidenced by multiple academic surveys [Reference Demyttenaere and Van Duppen10, Reference Camardese, Mazza, Zaninotto, Leone, Marano and Serrani13]. The dispositions of families and societal conceptions concerning DTD considerably influence the progression of the disorder [Reference Demyttenaere and Van Duppen10].

Raising awareness among the general public, specialists, and physicians about the importance of addressing these aspects in the management of DTD can help reduce the stigma associated with TRD and enhance the quality of life for patients. Physicians should become well-acquainted with DTD and its therapeutic options, as a deeper understanding of DTD and its treatment choices can lead to improved patient outcomes. As the scientific community continues to unearth the underlying intricacies, there’s hope that future endeavors will lead to better diagnostic tools, more effective treatments, and a deeper understanding of the disorder. At present, there is not a clear classification or specific taxonomy for DTD. This absence leads to diagnostic uncertainties and hinders clinical research, underscoring the need for further studies and detailed analyses. As a result, it is essential to develop new research methodologies and select appropriate experimental designs to accurately assess causal inferences and the applicability of clinical study findings [Reference Cosgrove, Naudet, Högberg, Shaughnessy and Cristea14]. In the future, the primary challenges will focus on the management of DTD and the optimization of treatments [Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood15].