Difficult-To-Treat Depression. Scoping Review

Abstract

Objective

Recently, several academics have recommended that the concept of difficult-to-treat depression (DTD) should be considered in some of the cases where achieving or maintaining remission of depressive symptoms is not possible. In 2020, a consensus statement, not based on a formal process and systematic review defined difficult-to-treat depression as “depression that continues to cause significant burden despite normal treatment efforts”. In addition to addressing symptom control, interventions for DTD should also target other factors, including the management of psychiatric and medical comorbidities, psychosocial functioning, self-esteem, and self-management strategies. The purpose of this scoping review is to explore the scientific literature, which is still unclear and vague, regarding the pathophysiology and treatment of difficult-to-treat depression, providing a summary of its current conceptualization. This represents a cultural and scientific shift that offers clinicians and researchers valid and up-to-date study criteria, thus expanding upon the model of treatment-resistant depression (TRD). Consequently contributions, concepts, theories and gaps of the state of the art in the description of difficult-to-treat depression have been summarized here.

Method

A research study was conducted using PubMed, Scopus, PsycINFO, Cochrane Library, and Open Grey databases to identify and examine articles reporting key features related to the recent concept of difficult-to-treat depression. The research covered a period of time between January 1, 2013, and March 1, 2023. Based on a formal checklist, two researchers independently assessed the eligibility criteria to determine which studies to include or exclude in this search. Further data evaluations were conducted for the articles that were deemed to have the most comprehensive descriptions.

Results

The results of the research yielded a body of literature that provides a clear definition of difficult-to-treat depression and insights into its clinical application and research perspective.

Conclusions

DTD represents a cultural and scientific shift that provides clinicians and researchers with valid and up-to-date study criteria that allow the extension of the treatment-resistant depression (TRD) model. The main difference lies in the operational process of assessment and intervention in the depressive syndrome in relation to the search for a therapeutic response. The results of this review show that DTD is a theoretically and clinically useful conceptualization for depressive syndromes that are not just simply resistant to treatment. This clinical condition entails a novel clinical therapeutic approach for specific patients and may be used throughout the world to help recognize this clinical condition while optimizing overall care for these patients. However, as we have highlighted, in the absence of RCTs and further observational studies, it is desirable that DTD be further investigated and defined..

Introduction

Depressive disorder is a generic term used to describe a category of psychiatric disorders characterized by the presence of depressive and/or anhedonic symptoms combined with other cognitive, vegetative and psychomotor symptoms. Depression is widely prevalent in Western society and ranks among the leading causes of disability worldwide (Mrazek et al., 2014). Despite adhering to the diagnostic criteria of DSM-5 and ICD-11, depressive disorders exhibit significant variability in terms of emotions, cognitions, and physical manifestations, often demonstrating marked differences among individuals. Even within Major Depression, which represents only a subset of depressive disorders and is classified according to DSM-5, clinical heterogeneity can be observed during acute episodes and throughout the course of the illness. This condition manifests through broad symptom profiles that can range from mild to moderate to severe, exhibiting diverse responses to treatments, levels of psychosocial dysfunction, suicidal thoughts, physical complications, and potential worsenings in disease progression (Seligman & Nemeroff, 2015); (Paganin et al., 2022). Depression affects millions of individuals worldwide, encompassing both genders and all age groups. According to the Global Burden of Disease Study, approximately 258 million people experienced depression in 2017 (Liu et al., 2020). Furthermore, in 2020, the COVID-19 pandemic contributed to a 28% increase in cases of Major Depressive Disorder (MDD), with higher prevalence among women and young individuals (Santomauro et al., 2021). The response to drug therapies for major depression disorder is not always optimal. A depression failing to respond to therapy is referred to as Treatment Resistant Depression (TRD). Resistant depression has not always been related only to MDD, but has also been considered in other forms of depression (Kielholz et al., 1978); (Souery et al., 1999); (Souery et al., 2006). The definition of TRD has historically been unclear and clinically uncertain, with interchangeable therapeutic approaches (Gaynes et al., 2020). Recently, TRD has been defined by the EMA (guideline-clinical-investigation-medicinal-products-treatment-depression-revision-2_en.pdf, s.d.) as failure (less than 25% reduction in symptoms as measured by the 17-item Hamilton Depression Scale) to respond at least two courses of antidepressants of adequate dose and duration. Anyway, over time different classifications have been made and currently there is no single universally accepted definition of TRD (Paganin et al., 2022). One study identified 155 definitions of treatment-resistant depression, with the number of failed treatments ranging from one to more than five (Brown et al., 2019). This uncertainty about TRD has led to inconsistent research over time, where it is unclear how pharmacological, psychotherapeutic, and neurostimulatory interventions should be considered in terms of differential efficacy according to the degree of treatment resistance of depression (McAllister-Williams et al., 2018). There is also no agreement on which psychotherapies should be included and how they should be counted in the definition of TRD (Brown et al., 2019) and there is no common consensus on the definition of therapeutic response and the appropriateness of the type, dosage and duration of the various treatments available (Gaynes et al., 2020). Finally, it should be considered that newly added instrumental and pharmacological therapeutic approaches are more expensive and/or invasive and raise economic and choice issues regarding the severity of the disease to be treated, leading to a further degree of disparity between the treatments provided and the related research (Rush et al., 2019). A conceptually different model that could overcome the idea of TRD is represented by Depression Difficult to Treat (DTD), which sees depression as treatable (difficult but not impossible) by recognizing special treatment beyond the standard treatment pathway, see table 1.

Table 1.

Comparison of conceptual models between DTD TRD reworked by Rush et al., 2019 and Demyttenaere and Van Duppen 2019

Terminology	Treatment-resistant depression (TRD)	Difficult-to-treat depression (DTD)
Concepts	“re-sistere”: to oppose of the patient or of the disease. Immobilism attributed to the disease or to the patient?	“tractare”: collaborative concept between patient, family and therapist. Cooperation
Models	Acute phase	Chronic phase
Approaches	Mainly biological Biomedical treatment	Biopsychosocial biomedical treatment Ability to deal with depression Functional recovery Optimization of symptomatic control Reducing the impact of symptoms
Endpoint	Categorical (remission or non-remission)	Dimensional (gradability of response)

For some researchers, when a patient's depression proves resistant to treatment, it is important to identify the underlying reasons for the persistence of resistance and determine the best utilization of all available interventions, including self-help settings, psychotherapeutic approaches, pharmacological interventions, and neurostimulation techniques. The goal is not only to alleviate the symptoms of depression but also to improve the patient's functioning and quality of life (Rush et al., 2019). In cases where patients do not respond to drug treatment, resistance can be attributed to pharmacokinetic or pharmacodynamic mechanisms. However, other non-biological factors may also contribute, reflecting a confluence of psychological and sociocultural influences that affect the patient's clinical trajectory and exacerbate issues arising from their medical condition. Non-response to pharmacological treatment, somatic therapies, and/or psychotherapies often suggests the presence of additional factors, such as biological resistance, diagnostic inaccuracies, limitations of current therapies, psychosocial variables, a history of childhood maltreatment or trauma, job dissatisfaction, physical and mental comorbidities, personality disorders, concurrent substance use, and non-compliance with treatment (Rush et al., 2019). In-depth clinical investigation is essential to understand the nature of the depressive state. Through a comprehensive examination of the factors underlying treatment resistance, it becomes possible to devise an individualized intervention that addresses the specific elements hindering successful treatment of depression. This approach enables clinicians to evaluate the factors that contribute to the patient's resistance to previous treatment modalities (Dodd et al., 2021). In the treatment of difficult-to-treat depression (DTD), the primary emphasis lies on optimizing symptom control and reducing the burden associated with pharmacological interventions, especially in cases where achieving complete remission is not feasible. This approach shares similarities with the management of chronic somatic diseases (McAllister-Williams et al., 2020). Additionally, some authors highlight how the terminology of "resistant depression" can be stigmatizing as it assigns blame for resistance either to the disorder itself or to the patient (Demyttenaere & Van Duppen, 2019). The importance of having operational, valid, and appropriate criteria in terms of psychopathology, therapy, and clinical governance is increasing within the field of depressive disorders. Therefore, it is necessary to reassess models, approaches, outcomes, and even terminologies. Considering the growing attention in this area and the absence of a systematic review, the objective of this scoping review is to examine, interpret, and synthesize the most recent scientific literature regarding the definition of "difficult-to-treat depression". By doing so, this review aims to shed light on the concepts, theories, and gaps present in the current body of knowledge. Furthermore, the review begins by distinguishing "difficult-to-treat depression" from "treatment-resistant depression", which still lacks clarity and specificity from both pathophysiological and therapeutic perspectives.

Methods

In general, scoping reviews are commonly employed for "reconnaissance" purposes, which involve clarifying definitions and conceptual boundaries within a specific topic or field. Unlike systematic reviews, scoping reviews do not focus on selecting the best evidence in a particular field. Instead, they provide a broader description of the research activities conducted in that field, including various study methodologies, without assessing quality and biases. Within a scoping review, the exploration of methodologies used in research related to the examined topic or field, as well as the identification and analysis of knowledge gaps, can serve as a preliminary phase to a systematic review. Scoping Reviews are particularly valuable when there hasn’t been a comprehensive literature review or when the nature of the literature is complex or heterogeneous, making a more precise systematic review of the evidence unsuitable. This Scoping Review was conducted in accordance with the PRISMA Extension for Scoping Review criteria (Tricco et al., 2018), involved searching PubMed, Scopus, PsycINFO, Cochrane Library and Open Gray databases for grey literature between 1st January 2013 and 1st March 2023. The search strings used in each database were formulated based on a priori defined key terms that align with the review objectives.

In PubMed, the search for each term was extended to “All Field”, including MeSH terms, and included only English-language literature published in the last 10 years. The string were based on the combination of more of the key terms which met the objectives of the review: ("Depressive Disorder, Treatment-Resistant/ classification"[Majr] OR "Depressive Disorder, Treatment-Resistant/diagnosis"[Majr] OR "Depressive Disorder, Treatment-Resistant/economics"[Majr] OR "Depressive Disorder, Treatment-Resistant/ epidemiology"[Majr] OR "Depressive Disorder, Treatment-Resistant/history"[Majr] OR "Depressive Disorder, Treatment-Resistant/therapy"[Majr] ) OR ("Difficult-to-treat depression") OR ("Quasi-tenacious depression") PUBMED 01/03/2023.

In Scopus, the literature search was extended to “Title, Abstract, Keyword” and restricted to human studies written in English within the last 10 years. ( ( "Treatment-resistant depression" ) OR ( "difficult-to-treat depression" ) OR ( "quasi-tenacious depression" ) ) AND ( concept* OR definition OR reconcept* OR management* OR assess* OR identif* OR diagnosis* ) ) AND ( LIMIT-TO ( SRCTYPE , "j" ) OR LIMIT-TO ( SRCTYPE , "p" ) ) AND ( LIMIT-TO ( SUBJAREA , "MEDI" ) OR LIMIT-TO ( SUBJAREA , "PSYC" ) OR LIMIT-TO ( SUBJAREA , "MULT" ) OR LIMIT-TO ( SUBJAREA , "HEAL" ) ) AND ( LIMIT-TO ( LANGUAGE , "English" ) ) AND ( LIMIT-TO ( EXACTKEYWORD , "Major Depression" ) OR LIMIT-TO ( EXACTKEYWORD , "Humans" ) OR LIMIT-TO ( EXACTKEYWORD , "Treatment Resistant Depression" ) OR LIMIT-TO ( EXACTKEYWORD , "Depressive Disorder, Major" ) ) AND ( LIMIT-TO ( PUBYEAR , 2023 ) OR LIMIT-TO ( PUBYEAR , 2022 ) OR LIMIT-TO ( PUBYEAR , 2021 ) OR LIMIT-TO ( PUBYEAR , 2020 ) OR LIMIT-TO ( PUBYEAR , 2019 ) OR LIMIT-TO ( PUBYEAR , 2018 ) OR LIMIT-TO ( PUBYEAR , 2017 ) OR LIMIT-TO ( PUBYEAR , 2016 ) OR LIMIT-TO ( PUBYEAR , 2015 ) OR LIMIT-TO ( PUBYEAR , 2014 ) OR LIMIT-TO ( PUBYEAR , 2013 ) ) SCOPUS 01/03/2023.

In the Cochrane Library, the literature search was conducted from 2013 to 2023 in the Cochrane Reviews section of the database under “Title, Abstract, Keyword” without further restrictions, with the following string: difficulty to treat OR treatment resistant depression. COCHRANE LIBRARY 01/03/2023.

In PsycINFO, the specific string was searched in any field: (treatment resistant depression AND difficult to treat depression AND Age Group: Adulthood (18 yrs & older) AND Year: 2013 To 2023. PSYCHINFO 01/03/23.

For Open Grey, the following keywords were searched: “difficult-to-treat depression” and “treatment-resistant depression” with the same time frame as the other searches. OPEN GREY 01/03/2023.

For the eligibility criteria, we included studies that focused on treatment failure in adult patients with major depression, taking into account the definitions of treatment-resistant depression and difficult-to-treat depression provided in the last decade in Europe, North America, and Australia. We specifically considered studies that classified and described difficult-to-treat depression, limiting our selection to studies involving adult patients and excluding those related to war-related trauma and physical trauma. Additionally, we excluded studies analyzing children and adolescents to prevent bias related to developmental cognitive processes. We reviewed all titles and abstracts and obtained the full text of potentially relevant papers.

Our search yielded a total of 3235 potentially relevant records, of which 1532 were excluded as duplicates and 1623 were excluded as irrelevant based on the title or abstract. The remaining 80 studies underwent a detailed evaluation. Among these, 57 were excluded as they did not meet the eligibility criteria, while the remaining 23 studies met the inclusion criteria. The searches were conducted until March 1, 2023. We screened all titles and abstracts and obtained the full text of potentially relevant articles. Each paper was independently read and evaluated by two researchers to determine inclusion or exclusion in this research. All papers that met the inclusion criteria were thoroughly reviewed, including review articles, research articles, original articles, meta-reviews, editorials, letters, and viewpoints. This scoping review has identifi ed the scientific literature that describes the new conceptual model of diffi cult-to-treat depression. The included studies strongly support efforts to improve its clinical definition and its applicability in clinical care, see figure 1 and summary table of the studies included in this scoping review.

Figure 1.

PRISMA-ScR Flow-Chart

Results

In the past, the term DTD was utilized interchangeably with TRD causing confusion among clinicians and further complicating the already uncertain definition of TRD (Moeller et al., 2022; Souery et al., 1999). However, in recent years, there has been a development in the taxonomic and conceptual specifi city of DTD, largely attributed to the work of Rush, McAllister-Williams, Demyttenaere, et al. They have proposed an internationally recognized consensus statement that advocates for the adoption of the clinical model of DTD, which is based on a comprehensive list of prognostic factors associated with the patient, the disorder, and the treatment (McAllister-Williams et al., 2020): (Demyttenaere & Van Duppen, 2019), although it is not always clear how these are combined to arrive at a clinical assessment.

Theorizing the model study of DTD it is crucial to emphasize the need for modifi cations the methodological approach compared to the past. These modifi cations should include the incorporation of various operational criteria that take into account the level of agreement among different experts within the study group. Additionally, it is important to include individuals who have firsthand experience with depression, known as people with lived depression (PWLD), within the study group. Furthermore, it is essential to establish precise and unambiguous operational criteria to identify key aspects such as response to treatment, partial response, and no response. Other factors that require clear definition include the number of antidepressant treatments, inclusion/exclusion criteria, presence of medical and/or psychiatric comorbidities, validation of appropriate psychometric and evaluative instruments, characteristics of pharmacotherapy, outcome criteria, and evaluation of the effectiveness of new treatments. In relation to DTD, it is crucial to explore the identification of biomarkers and evaluate the neurobiological aspects associated with different forms of depression. These considerations play a vital role in developing a comprehensive understanding of DTD and advancing research in the field (Rush et al., 2022; Sforzini et al., 2022). DTD is not a binary condition, but rather exists along a continuum of therapeutic response. This continuum includes complete response, partial response, and no response. By incorporating this conceptual framework, along with a systematic staging of treatment resistance, it becomes possible to consider the presence of various risk factors and comorbidities. These additional factors contribute to the complexity and criticality of managing DTD, highlighting various clinical challenges (Rush et al., 2019), see table 2.

Table 2.

Evaluation proposal for potential DTD from Rush et al., 2019

Evaluation proposal for potential difficult-to-treat depression

Confirmation of psychiatric diagnosis

Evaluation of the adequacy of previous pharmacological indications (dose and duration)

Confirmation of adherence to previous therapeutic indications

Consider pharmacogenetic testing or blood drug monitoring

Evaluation of co-occurring psychiatric conditions requiring treatment

Assessment of current general medical conditions requiring treatment

Evaluation of general medical conditions that are undiagnosed and may cause depression

Assessment of current environmental stressors that need remediation

Studies Included in this Scoping Review

N.	Year Authors, of Publication Studies,	Studies	Scientific Magazines	Nationality Publisher
1	Casey et al., 2013	Review Article	Medical Journal of Australia	Australia
2	Negele et al., 2015	Research Article	Depression Treatment Research and	UK
3	Camardese et al., 2016	Original Article	Nordic Journal of Psychiatry	UK
4	McAllister-Williams et al., 2018	Analysis	The British Journal of Psychiatry	UK
5	Perlman et al., 2019	Meta Review	Journal of Affective Disorders	NL
6	Rush et al., 2019	Review Article	Australian & of New Psychiatry Zealand Journal	Australia
7	Demyttenaere e Van Duppen, 2019	Review Article	Neuropsychopharmacology International Journal of	UK
8	Fava & Rafanelli, 2019	Editorial	Psychotherapy Psychosomatics and	Switzerland
9	Fava et al., 2020	Editorial	Psychotherapy Psychosomatics and	Switzerland
10	McAllister-Williams et al., 2020	Review Article	Journal of Affective Disorders	NL
11	Dodd et al., 2021	Review Articles	The World Journal Psychiatry of Biological	UK
12	Cosgrove et al., 2021	Letter	The Lancet Psychiatry	NL
13	McAllister-Williams et al., 2021	Letter	The Lancet Psychiatry	NL
14	Rush et al., 2022	Review Article	Psychological Medicine	UK
15	McAllister-Williams, 2022	Review Article	Neuropsychopharmacology European	NL
16	Riveros et al., 2022	Review Article	Antioxidants	Switzerland
17	Moeller et al., 2022	Review Article	Nordic Journal of Psychiatry	UK
18	Sforzini et al., 2022	Review Article	Molecular Psychiatry	USA
19	Costa et al., 2022	Original Article	Journal of Psychopharmacology	UK
20	Rosana Silva. 2022	Original Article	Mendeley Data	NL
21	Cohen et al., 2022	Research Article	Journal of Interpersonal Violence	USA
22	Arjmand et al., 2023	Viewpoint	European Psychiatry	UK
23	Sackeim et al., 2023	Original Article	Psychological Medicine	UK

In accordance with standard medical practice, when a patient does not respond to treatment intervention, it is crucial to reevaluate the diagnosis. This includes considering alternative diagnoses such as bipolar disorder and ruling them out through careful evaluation. Comorbidities can play a role in treatment resistance, and it is necessary to address them as part of the management plan. Additionally, psychosocial factors should be appropriately recognized and addressed, as they can impact the nature of treatment resistance. (McAllister-Williams et al., 2018). It is now possible to develop a taxonomy that allows a clear identification of the specific characteristics that distinguish patients with DTD from patients who do not have DTD (Rush et al., 2022).

The following factors should be taken into consideration when assessing (DTD): the course of depression, with variability of symptoms; the presence of anhedonia and anxiety; comorbid psychiatric and/ or general medical conditions, including substance use disorders; appropriately evaluated medication intake and functional impairment. In the medical history, attention should be paid to the number, sequence, and types of treatments given, treatment failures, family history, and treatment adherence (Perlman et al., 2019; Rush et al., 2022). It is also particularly important to identify previous emotionally significant childhood trauma (Negele et al., 2015; Cohen et al., 2022; Silva, 2022). Various aspects that may lead to difficult-to-treat depression include poor acute response to initial drug treatment, risk of relapse despite ongoing treatment, use of multiple antidepressants, chronicity, poor quality of life with daily dysfunction, high risk of suicide, substance use, high levels of psychiatric disorders and comorbid medical disorders, and frequent use of mental health services (Costa et al., 2022). The treatment of these patients requires a complex multidisciplinary approach that can benefit from the contribution of new tools of personalized medicine. It is also likely that the combination of psychological treatments with pharmacotherapy improves recovery rates in hard-to-treat depression (Casey et al., 2013). The conceptual model of resistant depression has had two clinical consequences. The first has been the development of medications designed to combat treatment resistance (e.g., ketamine/esketamine) that would be unlikely to find a place in a classic RCT trial of treatment for nonresistant depression (Fava et al., 2020). The second consequence has been the assumption that treatment with any antidepressant is equitable and that non-response is solely attributable to patient characteristics. This belief has led to an escalation in medication trials, resulting in what is known as "cascading iatrogenesis" or "iatrogenic comorbidity" (Engel, 1977), for example, unfavorable changes in the course and characteristics of treatment response that are correlated with previously administered therapies (Fava & Rafanelli, 2019). According to this concept, treatment resistance often leads to an escalation in antidepressant medication usage rather than a reconsideration of treatment options. However, it is crucial to take into account the biopsychosocial model, which recognizes the importance of various factors in treatment outcomes, including therapist behavior, the patient-doctor relationship, environmental and cultural influences, social isolation, and treatment costs (Fava et al., 2020). Furthermore, due to the predominant focus on biological treatments in research, evidence for psychosocial therapies applicable to difficult-to-treat depression remains limited. However, some studies suggest that combining psychosocial treatments with pharmacotherapy can improve recovery rates in DTD, and psychological therapies may prove highly beneficial in these cases (Casey et al., 2013).

The initial intervention in DTD should prioritize the treatment of depressive symptoms and help patients learn effective coping strategies to manage their symptomatology. In this case, the main goal of treatment shifts from achieving remission to achieving optimal symptom control and improving quality of life (McAllister-Williams et al., 2020),

Quality of life, as defined by a 1995 WHO working group, The World Health Organization Quality of Life Assessment, refers to "an individual's perception of their position in life in the context of the culture and value systems they live in, and in relation to their goals, expectations, standards, and concerns" (WHOQOL, 1995). Therefore, the objective is also to enhance personal, family, work, and social functioning (McAllister-Williams, 2022). Physicians often prioritize the alleviation of depressive symptoms, but it is essential to seek physician-patient agreement as the primary factor in defining treatment (Demyttenaere et al., 2015). Treatment decisions in such cases should consider the patient's perspectives, in collaboration with clinicians, through personalized interventions that deconstruct the factors contributing to difficult-to-treat depression (Dodd et al., 2021) Exploring all available treatment options is crucial to optimizing outcomes when achieving symptomatic remission is unlikely. Family involvement has shown effectiveness in treating complex and severe forms of depression in numerous studies (Camardese et al., 2016) The behavior of family members, along with the stigma surrounding depression, strongly influences the illness's outcome (Demyttenaere & Van Duppen, 2019).

The key points that have been suggested for the management of DTD in the 2020 international consensus statement (McAllister-Williams et al., 2020).

1. Achieving optimal symptom control involves using treatments that include conventional approaches such as first-line pharmacotherapy (with increased dose, switch, or augmentation), psychotherapy (with high-intensity psychotherapy with or without medication), or neurostimulation (including ECT). Subsequently, unconventional treatments such as new drugs, psychotherapies, or neuromodulation can be considered.

2. Identifying symptoms associated with worse outcomes and specifically intervening on them. In particular, it is important to assess and treat anxiety and pain.

3. Identifying symptoms that affect quality of life and intervening on them. In particular, it is important to assess and treat sleep problems, fatigue, and cognitive problems.

4. Managing comorbidities to reduce the overall burden of symptoms. This may include assessing and treating physical health problems, substance abuse, comorbid mental illnesses, and iatrogenic problems.

5. Optimizing long-term outcomes by ensuring regular follow-up and continuous treatment.

6. The use of self-management techniques to empower patients involves encouraging patients to actively participate in the management of their mental health. This can be achieved by:

   • - Promoting a critical perspective towards negative thoughts.

   • - Implementing behavioral activation strategies.

   • - Facilitating active engagement with the community.

   • - Promoting good sleep hygiene.

   • - Encouraging regular exercise.

   • - Emphasizing the importance of a healthy diet.

   • - Enhancing coping skills for residual symptoms.

   • - Considering occupational or interpersonal adjustments based on individual capabilities.

   • - Utilizing online resources for managing depression, anxiety, and sleep.

7. Providing a sense of containment and ensuring integrated mental health services for comprehensive consideration of treatment options. Construct an individual management plan and highlight the role of the patient in long-term management. This can be accomplished by:

   • - Ensuring easy access to primary and secondary health-care services.

   • - Establishing a clear understanding of how to access the treatment pathway.

   • - Involving and supporting the patient's partner, family, or other appropriate individuals in their care.

   • - Facilitating access to highly specialized services for non-conventional treatments.

8. Regular review of the patient's diagnosis and treatment is crucial. This includes formally assessing the severity of symptoms and their impact on psychosocial functioning, reevaluating the diagnosis when necessary, and screening for comorbidities. It is also important to evaluate predisposing, precipitating, and perpetuating factors as part of the ongoing assessment and management process.

The group of psychiatrists from around the world who met to agree on the definition of DTD as “Depression that continues to cause significant burden despite normal treatment efforts” has made recommendations on how best to treat DTD (McAllister-Williams et al., 2020).

The main objectives in DTD are to:

• - Investigate optimal symptom control: in some cases, even a 25% decrease in symptoms can reduce suicidal thoughts and enable the patient to live independently and even work.

• - Reduce the risk of relapse, through frequent reevaluations and considerations of the direction of treatment adopted, involving the doctor and the patient in a shared decision-making process, explaining both the adverse effects and the clinically significant benefit of the treatment.

• - Optimise psychosocial functioning by restoring a meaningful life, increasing self-esteem, and supporting the self-management strategies and patient empowerment necessary for long-term management of DTD.

Some authors raise concerns regarding the therapeutic choices for DTD and ask whether such principles should not be applied to the management of all types of depression, not just DTD or TRD (Malhi & Bell, 2021). Others recognise the model proposed by the international consensus statement but continue to maintain the central importance of the response to pharmacological therapy, theorising “response tenacity” as a potential barrier in reacting to a particular therapeutic strategy (Arjmand et al., 2023). Still others hypothesise that the lack of response in difficult-to-treat depression is linked to oxidative stress in the brain. Recent research on the possible role of antioxidants in treating and preventing depression shows, through preclinical and clinical trials, the potential effects of different antioxidant and anti-inflammatory biomolecules as antidepressants, with a particular focus on difficult-to-treat depression and treatment-resistant depression (Riveros et al., 2022). However, still more knowledge is needed about the characteristics and effective treatments of these patients. At present, when treating DTD, the clinician should rule out pseudo-resistance and consider proven evidence-based interventions before attempting alternative therapeutic strategies (Moeller et al., 2022). The considerable complexity of defining therapeutic response encompasses the difficulties both of defining the evaluation criteria (response-remission) and of choosing the inclusion criteria (first episode-recurrence). Clinical cases classifiable as DTD are delimited by the number of non-responses to treatment and by the types of pharmacological, psychological and ECT therapy. Non-response to treatment could be due to other conditions that do not facilitate the therapeutic response on the pharmacodynamic level (Sackeim et al., 2023); (Castle et al., 2013). The role of medical diseases that favour the onset of depression is not yet clear, and it needs to be clarified whether they predominantly play the role of a “stress” factor that fosters depressive syndrome or have “causal” links related to their common etiopathogenetic aspects.

Discussion

The term "difficult-to-treat depression" has been employed in scientific literature with a degree of approximation and generality. It has frequently been used interchangeably with "treatment-resistant depression" to refer to forms of depression where patients are unable to continue drug treatment due to factors related to their personal, social, and economic circumstances, as well as various types of medical-psychiatric comorbidity (Grote & Frank, 2003). “Difficult-to-treat depression” appears to be a more empathetic term than “treatment resistant depression” and the underlying concept represents an opportunity to equip all clinicians and researchers within the field with valid and appropriate operational criteria. Since 2002 at a conference on treatment-resistant depression in San Francisco, the idea of a semantic difference between TRT and DTD was promoted by considering DTD with greater attention, the concept of DTD has gained prominence by emphasizing the patient's perspective and the challenges associated with identifying the primary concerns frequently expressed by patients and their families (Kupfer & Charney, 2003). Over the years, there have been ongoing efforts to delineate the defining characteristics of "treatment-resistant depression" primarily based on pharmacotherapy response (outcome). However, this narrow "response perspective" in TRD fails to consider the prognostic significance of the clinical trajectory and the treatment history, which can involve a potentially endless cycle of therapeutic attempts with escalating side effects. This approach disregards the underlying factors contributing to poor treatment outcomes (McAllister-Williams, R.H., Aaronson, S., Conway, C. et al., 2021). The DTD model provides for a regular review and reassessment of treatment, shifting the focus from remission, to optimization of symptom control and maximization of psychosocial functions (Sackeim et al., 2023). While, some reservations exist, difficult-to-treat depression may not adequately address the uncertainty associated with the treatment-resistant depression label: “...we are concerned that difficult-to-treat depression may be a case of broadening disease definitions...lowering diagnostic thresholds amplify the need to treatments... and expand the pool of potential patients”… (Cosgrove et al., 2021). The proposed definition and treatment model for TRD does not derive from a systematic review or Delphi technique and this leads to some criticisms (Cosgrove et al., 2021); (McAllister-Williams, R. H., Arango, C., Blier, P. et al., 2021). The criteria for identifying DTD are broad and more amenable to subjective interpretation than the criteria for treating treatment-resistant depression, making it unlikely for clinicians and researchers to implement them rigorously or consistently. The pharmaceutical industry can easily take advantage of these relaxed criteria by designing trials for the production of new drugs for this purpose: “...allowing the use of vague diagnostic criteria for controversial conditions creates unnecessary challenges when regulators need to review expensive therapies with obvious risks and uncertain benefits”… (Cosgrove et al., 2021).

In DTD cases the co-occurrence of various factors such as age, sex, medical and psychiatric comorbidity, traumatic experiences, drug use, etc. is relevant. The presence of such risk factors can prevent both a correct assessment of the patient and a useful operational definition of therapeutic interventions that could be a useful element to modify the negative evolution of depression. From what has been examined in the literature, the sequence of the various pharmacological therapies adopted is not clear. That is, if the choice and administration of an antidepressant drug is arbitrarily defined by the doctor, or meets criteria of efficacy or clinical appropriateness (detected on the basis of the presence of certain psychopathological dimensions) or is determined by the presence of comorbid medical conditions. It is important to consider the course of comorbid disorders as they can be negatively affected by depressive syndrome, both in their clinical expressiveness and in their severity. Of course, the percentage frequency of comorbidity of each medical disorder leads to the verification of different etiopathogenetic and neurobiological pathways between these and depressive syndrome. In addition, further clarification would be needed in the definition of the criteria for response and remission, taking into account the persistence of significant residual symptoms on the psychopathological level (anhedonia, apathy, loss of interpersonal relations, etc.) and the possibility of recurrence of psychiatric disorder.

Conclusions

The term difficult-to-treat depression (DTD), often used interchangeably with treatment-resistant depression (TRD), has led to confusion in the field of psychiatry. However, the recent redefinition of DTD represents a significant cultural shift closely tied to clinical practice and therapy. Some authors have emphasized a more substantial distinction between the two definitions, enabling psychiatrists to better understand the conceptual model of DTD. The goal is to empower patients to effectively manage their illness and live fulfilling lives.

This conceptual change goes beyond semantics and represents a genuine cultural revolution. The distinction helps identify complex cases that are challenging to treat not only due to a lack of therapeutic response but also because they require multidisciplinary interventions involving the patient and their family. This comprehensive approach considers coexisting psychiatric and medical conditions, contextual environmental factors, treatment non-adherence, as well as issues such as low self-esteem, hopelessness, and cognitive disengagement. It is crucial to bring together professionals from different disciplines in a collaborative dialogue, utilizing all available tools to support individuals with DTD when medications alone fail to meet their clinical needs. This new approach to resistance certainly includes the use of treatments for organic pathologies, psychotherapies and instrumental therapies, together with functional rehabilitation alongside other ways of promoting neuronal plasticity. These are to be explored and made increasingly usable and well-known, including by non-clinicians. In the coming years, even if the term TRD still remains widely used in research into developing new drugs, it is desirable to have constant research with continuous systematic reviews regarding DTD, while bearing in mind the risk that a new clinical condition and/or diagnosis could be an opportunity for the pharmaceutical industry to influence future studies. The results of this scoping review bring out the importance henceforth of rethinking treatment-resistant depression in favour of an operational concept of evaluating and treating depressive syndrome in clinical practice and academia. There is a clear need for comprehensive investigation into therapeutic responses to treatment in patients with difficult-to-treat depression (DTD). This can be achieved through conducting observational studies that assess the impact on quality of life, as well as randomized clinical trials (RCTs) comparing the effectiveness of different treatment modalities, including pharmacological, psychological, and instrumental interventions. These studies should focus on identifying the most promising approaches for managing DTD. Researchers and clinicians should be encouraged to go beyond solely analyzing resistance in depression and instead pursue broader research aimed at developing comprehensive management strategies for DTD. This involves exploring and evaluating all possible treatments that could be applicable to difficult-to-treat depression. By adopting a multidimensional and inclusive approach, we can enhance our understanding of the condition and identify effective interventions that can improve outcomes for individuals living with DTD. Furthermore, additional consensus conferences focusing on DTD are desirable to bridge various areas of neuroscientific research and explore the integrated treatment of depression with other disorders that may occur in the context of organic and neurological diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and others.