Depression: beyond sadness

Depression, in its broadest sense, is a psychological condition marked by feelings of sadness and lack of interest in life's activities.^{Reference Salik and Marwaha1} Although it is common for individuals to experience transient periods of sadness or ‘feeling down’, these emotions are generally short-lived and can be related to specific events or circumstances. When these feelings become pervasive and persistent and begin to interfere with daily functioning, the progression from a mere emotional state to the clinical condition of depressive disorder occurs. This is a syndrome involving significant disturbances in emotions, neurocognitive functions, physiological functions and behaviour, indicating dysfunctions in psychological, biological or developmental processes, according to the ICD-11² and DSM-5 TR.³ Depressive disorder is associated with considerable disability and dysfunction in the personal, emotional, family, work and social realms, necessitating clinical intervention and treatment when these exceed the normal variations of behaviour from an individual, social or cultural perspective.^{Reference Ormel, Kessler and Schoevers4} Biological factors such as imbalances in neurotransmitters or hormones and genetic predispositions, as well as external factors such as trauma, loss and prolonged stress, contribute to the transition from simple states of sadness to various depressive disorders.^{Reference Chand and Arif5} In the ICD-11, developed by the World Health Organization with a global clinical perspective, depressive disorders are grouped into several categories: single-episode depressive disorder, recurrent depressive disorder, dysthymic disorder, mixed depressive and anxiety disorder, premenstrual dysphoric disorder, other specified depressive disorders, and unspecified depressive disorders. In the DSM-5, developed by the American Psychiatric Association and dominated by an Anglophone-American perspective, depressive disorders are classified as follows: disruptive mood dysregulation disorder, premenstrual dysphoric disorder, persistent depressive disorder (dysthymia), major depressive disorder, substance/medication-induced depressive disorder, and depressive disorder due to another medical condition. Research has shown that the origin of depression lies in a complex interplay of genetic and environmental factors. A family history of depression increases the risk of developing the condition,^{Reference Namkung, Lee and Sawa6,Reference Pham and Gardier7} and factors including neuroinflammation, neurodegenerative diseases, daily stress and traumatic experiences are particularly significant in older adults.^{Reference Roman and Irwin8–Reference Harjono Hadiwiardjo and Damayanti10} Adverse childhood experiences (ACEs), including early traumas, have been recognised in terms of their impact on both post-traumatic stress disorder (PTSD) and depression.^{Reference Negele, Kaufhold, Kallenbach and Leuzinger-Bohleber11–Reference Juul, Hjemdal and Aune13} The interaction between genetic predisposition and environmental factors, particularly early life trauma (ELT), plays a fundamental part in the development of depressive disorders that are difficult to treat, making their management a complex challenge.

Approaches to difficult-to-treat depression

In the past, the term ‘difficult-to-treat depression’ (DTD) was used interchangeably with ‘treatment-resistant depression’ (TRD). However, a significant paradigm shift occurred in 2020 when an international consensus recommended expanding the TRD model to encompass a more comprehensive perspective.^{Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood14} The TRD model that emerged from studies by Thase and Rush^{Reference Thase and Rush15} was limited to individuals who showed resistance only to antidepressant medications or those who could not tolerate the initial drug. Thase and Rush proposed a five-stage model to address resistance to different classes of antidepressant. Over time, this model has been replaced by other classifications and has evolved and been variably defined to describe the failure of antidepressant pharmacological treatment in general. A systematic review identified 155 different definitions of TRD,^{Reference Brown, Rittenbach, Cheung, McKean, MacMaster and Clement16} whereas Wijeratne and Sachdev^{Reference Wijeratne and Sachdev17} noted that there are no formal diagnostic criteria for TRD, and one of its limitations is its exclusive application to acute treatments without considering the possibility of relapse after a transitional period of remission. Subsequently, Rush et al^{Reference Rush, Sackeim, Conway, Bunker, Hollon and Demyttenaere18} listed a series of considerations regarding the concept of TRD. They questioned whether a lack of response or remission could define a treatment as failed, how to consider cases where patients improve but then relapse, whether to include cases where a medication cannot be tolerated in the definition of TRD, and whether previously failed treatments should be considered. Furthermore, they noted that definitions of TRD generally do not include non-pharmacological treatments, such as psychotherapy and psychosocial interventions, stating that ‘TRD has no practical, actionable clinical implications other than to suggest attempting another, primarily pharmacological, treatment trial with a different intervention or combination’.^{Reference Rush, Sackeim, Conway, Bunker, Hollon and Demyttenaere18} Currently, clinicians and researchers tend to adopt the definition formulated at the turn of the millennium by Souery et al^{Reference Souery, Amsterdam, de Montigny, Lecrubier, Montgomery and Lipp19} and later adopted by the US Food and Drug Administration and the European Medicines Agency which defines TRD as the failure to respond to two or more antidepressant pharmacological regimens despite adequate dose and duration, as well as treatment adherence. In recent years, a significant transition from the TRD model to the DTD model has occurred. The DTD model highlights the importance of a perspective that transcends resistance to pharmacological treatments, favouring a broader and more inclusive approach to treating depression. It underscores the need to consider psychological, social and environmental factors that may influence the response to therapy. DTD is not conceived as a binary condition of therapeutic responses but rather as a continuum that includes full responses, partial responses and non-responses, thus shifting the focus of treatment from a curative model of symptom remission to a disease management model that emphasises functional improvement and quality of life, aiming for optimal symptom control without necessarily achieving complete elimination.^{Reference Paganin20} Currently, there are no uniform operational criteria used to precisely and measurably define DTD. However, the international consensus statement^{Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood14} proposed adopting a list of factors related to treatment, symptomatology and the patient to identify a clinical framework for DTD. A series of interventions were indicated, ranging from self-help methodologies to psychotherapies, pharmacological strategies, neurostimulation techniques and social interventions to support and facilitate access to general and specialised care and job integration. This will require an individualised intervention strategy that emphasises not only symptom remission but also improvement of the patient's psychosocial functionality. Whereas some patients may show a partial response to initial treatments yet remain functionally impaired, others may show no response. The clinical framework of DTD perceives the condition as treatable (albeit challenging) and underscores the need for personalised care and overcoming routine therapeutic paradigms. DTD encompasses a spectrum of severity and functional impairment, often coexisting with psychiatric or somatic comorbidities. Characterising DTD in clinical terms remains challenging and requires a sophisticated and multidimensional understanding.^{Reference Paganin, Signorini and Sciarretta21} This involves considering various aspects, including clinical manifestations, disease progression, biomedical elements, prognostic markers, neuropsychological aspects and treatment responses. Critical factors include the extent and duration of functional decline, symptom history, relapse patterns and the initial clinical profile, particularly the nature and number of unsuccessful therapeutic interventions, psychiatric and organic pathologies, and a history of childhood trauma. A prevalent observation among patients with TRD is a decline in the effectiveness of previously effective pharmacological treatments, suggesting changes in crucial neurobiological foundations. This observation also raises a concerning possibility: ineffective or partially effective treatments may induce neurobiological changes, reducing treatment responsiveness and exacerbating the intractability of depression.^{Reference Fava22–Reference Paganin, Signorini, Leccese and Sciarretta24} Treatment resistance can worsen, leading to increased chronicity. Unlike a single episode of depression that typically responds to treatment and has no lasting impact on personality, persistent depression, with or without appropriate intervention, can shape the clinical trajectory of DTD. Patients with DTD may develop maladaptive behavioural and cognitive patterns that intensify pessimism and negative self-perception. Essentially, depression perpetuates itself, amplifying self-destructive thought patterns and worsening the condition. In evaluating patients with DTD, it is important to consider the clinical presentation of depressive symptoms, with a specific focus on the incidence of anhedonia and anxiety, as well as psychiatric comorbidities and/or concurrent general medical conditions, including substance use disorders. Furthermore, a meticulous evaluation of pharmacological interventions and the patient's functional deterioration is warranted.^{Reference Paganin20} The DTD model proposes that in cases where the patient with depression remains unresponsive to treatment, it is important to identify the underlying causes. In the context of medical history, attention should be paid to the number and sequence of previous therapeutic attempts, the types and number of therapeutic failures, as well as family history and treatment adherence. In addition, it is particularly important to identify significant childhood emotional traumas.^{Reference Negele, Kaufhold, Kallenbach and Leuzinger-Bohleber11,Reference Cohen, McNeil and Menon25} Events that may occur during an episode of major depression and can lead to DTD include: poor acute response to initial pharmacological treatment, risk of relapse despite ongoing treatment, and the use of multiple antidepressants. These factors could be used to help identify affected patients and to recognise subgroups or spectra of patients, potentially together with use of neuroinflammation biomarkers. A specialised taxonomy for DTD could be developed on the basis of assessment of distinctive characteristics that separate DTD cases from non-DTD cases. Such considerations may include comorbid general medical conditions, the nature and severity of anxiety symptoms, the presence of anhedonia, the extent and chronicity of environmental stressors, concurrent substance use or misuse disorders, and a history of early trauma or abuse;^{Reference McAllister-Williams, Arango, Blier, Demyttenaere, Falkai and Gorwood14,Reference Rush, Aaronson and Demyttenaere26} these factors may interact with other characteristics of DTD, adding complexity to the presentation. Psychosocial determinants of health may act as perpetuating factors and thus warrant attention to improve treatment outcomes. These determinants can include chronic stressors related to occupation, marital status, financial conditions or health problems, as well as lifestyle-related factors such as sedentary behaviour and obesity (see Fig. 1 for a summary of these characteristics).

Fig. 1 Key factors associated with difficult-to-treat depression (DTD), including early life trauma.

Moreover, predisposing elements such as ELT may have persistent effects on DTD by compromising resilience and problem-solving abilities.^{Reference Negele, Kaufhold, Kallenbach and Leuzinger-Bohleber11} In patients with DTD, ELT events represent important risk factors that can exacerbate the condition or develop into comorbid disorders, further complicating clinical treatment of depression.^{Reference Rush, Sackeim, Conway, Bunker, Hollon and Demyttenaere18} A history of ELT can also influence the effectiveness of therapeutic approaches, potentially compromising treatment outcomes. A comprehensive assessment focusing on potential ELT and the possibility of medical and psychiatric complications is crucial to devising effective therapeutic strategies for patients with DTD.

Definition of ELT

The term ACE was introduced by Vincent Felitti and Robert Anda between 1995 and 1997 to describe various forms of childhood trauma with significant long-term effects on physical and mental health. Initially, ACEs encompassed seven domains: physical, sexual and emotional abuse; living with individuals experiencing mental illness or substance misuse; and having an incarcerated family member.^{Reference Felitti, Anda, Nordenberg, Williamson, Spitz and Edwards27} Over time, the definition expanded to include parental separation, neglect and societal factors such as poverty, community violence, homelessness and intra-community violence. The concepts of early life stress (ELS) and ACEs encompass a wide array of stress-inducing and negative events. These events include but are not limited to maltreatment, neglect, parental separation or loss, exposure to extreme poverty, starvation, and various forms of violence within domestic, community or educational environments. Such experiences can occur at any point from infancy and throughout adolescence. ELS and ACE thus serve as umbrella terms, covering a diverse range of stressful or adverse experiences. Conversely, ELT and childhood trauma have been defined with greater specificity, referring to events that inflict significant traumatic impact. These classifications are reserved for events that pose imminent risks of harm or death or significantly compromise the physical safety of the individual or others. Such traumatic events trigger profound responses of horror, fear or helplessness, overwhelming an individual's coping mechanisms. Examples include acts of terrorism, experiences of war, natural and human-made disasters, physical and sexual abuse, medical trauma, motor vehicle accidents, and direct exposure to acts of violence such as homicides or suicides. Traumatic experiences are an important public health concern owing to their high prevalence, with 30–40% of adults reporting significant adverse experiences during their early life according to the literature.^{Reference Agorastos, Pervanidou, Chrousos and Baker28} The differences between traumatic events and traumatic experiences have been elaborated in the scientific literature and in psychiatric disorder classification systems such as the DSM-5 TR and ICD-11. According to these classifications, traumatic experiences include repeated exposure to physical and/or emotional neglect, maltreatment and sexual abuse. Although these exposures may not match the intensity of singular traumatic events, they nonetheless predispose individuals to syndromes such as complex PTSD (C-PTSD). Recent research indicates a convergence between the concepts of ACEs – representing concrete situations of social, personal, and interpersonal distress that negatively affect a child's emotional development – and ELS and ELT; depending on their operational definitions and contextual factors, these experiences exhibit significant overlap, demonstrating the complex interplay between different forms of early life adversity and their potential to precipitate enduring psychological effects.^{Reference Desch, Mansuri, Tran, Schwartz and Bakour29,Reference Barton, Ehring, Reinhard, Goerigk, Wüstenberg and Musil30} ELT encompasses a range of experiences potentially harmful to those under 18 years old.^{Reference Kulkarni, Leyden, Gavrilidis, Thew and Thomas31} Epidemiological research has demonstrated a strong link between ELT and mental health issues throughout life,^{Reference Moore, Scott, Ferrari, Mills, Dunne and Erskine32} indicating that such traumas cause lasting changes to the hypothalamic–pituitary–adrenal (HPA) axis and affect neurophysiological and inflammatory responses.^{Reference Westfall and Nemeroff Charles33} Defined as any negative childhood experience with long-term harm potential (Table 1), these events can disrupt crucial developmental stages, affecting a child's emotional regulation and relationship-building.^{Reference Cruz, Lichten, Berg and George40} Trauma includes abuse, neglect, exposure to violence, and life upheavals such as parental divorce or unstable living situations, which may be further complicated by domestic violence or separation from caregivers.^{Reference Smith and Pollak39} Early traumas undermine a child's sense of security and can have profound effects on development and health. They also set the stage for stress-related disorders by altering neurodevelopment and mental health. Neurobiologically, trauma can disrupt stress response systems and reducing hippocampal volume, which is essential for stress management and memory.^{Reference Teicher, Samson, Anderson and Ohashi38} Genetic factors and gene–environment interactions, such as FKBP5 polymorphisms, can increase vulnerability to stress and affect cortisol regulation.^{Reference Juul, Hjemdal and Aune13} Epigenetic mechanisms such as DNA methylation play an equally important part in modulation of gene expression without altering the DNA sequence.^{Reference Paganin and Signorini45} DNA methylation is a process in which a methyl group is added to specific DNA bases, often resulting in decreased expression of the corresponding gene. In response to trauma or stress, changes may occur in the methylation of specific genes involved in the stress response, such as the NR3C1 gene that codes for the glucocorticoid receptor.^{Reference McGowan, Sasaki, D'Alessio, Dymov, Labonté and Szyf46} However, not all individuals who experience childhood trauma develop psychopathological disorders,^{Reference Jozefiaková, Kaščáková, Adamkovič, Hašto and Tavel42} and the course and outcomes of early traumas can vary enormously from one individual to another, owing to many complex factors including genetics, environment, personal resources, individual resilience; social support can have a protective role, mitigating the negative effects of trauma.^{Reference Jozefiaková, Kaščáková, Adamkovič, Hašto and Tavel42} Childhood trauma is associated with a wide range of physical health conditions including cardiovascular diseases, immune system dysfunctions, endocrine disorders, gastrointestinal issues, chronic pain and respiratory diseases.^{Reference Danese, Moffitt, Harrington, Milne, Polanczyk and Pariante44} The likelihood of developing specific mental health disorders, including depression, anxiety disorders, eating disorders, dissociative disorders, sleep disorders, attention-deficit hyperactivity disorder (ADHD), PTSD, C-PTSD, substance use disorders, and personality disorders, is influenced by childhood traumas.^{Reference Agorastos, Pervanidou, Chrousos and Baker28,Reference Wolff and Shi34,Reference Waldinger, Schulz, Barsky and Ahern47} These disorders can be addressed through a combination of psychological and pharmacological interventions, depending on the individual needs of the patient. Psychological interventions may include cognitive–behavioural therapy (CBT), exposure therapy, mentalisation-based therapy and emotion regulation therapy, whereas pharmacological therapy can be used to treat specific symptoms such as anxiety or depression.^{Reference Cruz, Lichten, Berg and George40,Reference McKay, Cannon, Chambers, Conroy, Coughlan and Dodd41} Treatment of early trauma always requires an integrated and personalised approach, taking into account the individual needs of the patient and their specific traumatic experiences. ELT is associated with various comorbidities, although there has been a particular focus on the heightened risk of developing PTSD and its severe form, C-PTSD.^{Reference Wolff and Shi34,Reference Thomaes, Dorrepaal, van Balkom, Veltman, Smit and Hoogendoorn37,Reference Waldinger, Schulz, Barsky and Ahern47,Reference McLaughlin, Koenen, Hill, Petukhova, Sampson and Zaslavsky48} Studies indicate that the prevalence of these disorders varies, with approximately 28% of adults who have experienced childhood abuse meeting the criteria for PTSD and 32% meeting those for C-PTSD.^{Reference Bernhard, Martinelli, Ackermann, Saure and Freitag35,Reference Haselgruber, Sölva and Lueger-Schuster36} Whereas PTSD typically stems from a single traumatic event and is characterised by symptoms such as flashbacks and hyperarousal, C-PTSD results from prolonged traumas and involves issues with emotional regulation and attachment. In addition, the repercussions of early trauma extend beyond the individual, encompassing intergenerational effects that affect the mental health and well-being of future generations.^{Reference Reese, Barlow, Dillon, Villalon, Barnes and Crandall43} Neuroendocrine dysregulation, which affects a range of physiological and psychological functions, has been identified as a factor contributing to the co-occurrence of depressive disorders and post-traumatic disorders.^{Reference Sherin and Nemeroff49,Reference Schiller, Ben-Shaanan and Rolls50}

Table 1 Effects of early life trauma, including neurobiological, psychological, cognitive and social impacts, comorbidities and intergenerational transmission

Given the absence of systematic reviews thoroughly exploring the interplay between ELT and DTD, we considered that a scoping review specifically focused on this subject would be timely and relevant. In this review, we aimed to catalogue and analyse the body of existing studies, highlighting both well-established areas of research and those that are emerging or insufficiently explored. Moreover, we endeavoured to provide an updated compendium to outline both current knowledge and information gaps and guide future research. Overall, the goal was to broaden our understanding of the impacts of ELT on DTD and to facilitate the development of targeted and effective therapeutic approaches based on robust and relevant evidence.