Thirty years ago Robert Kellner and I introduced the concept of staging in psychiatry [1]. The paper reflected the insights that I had gained in assessing prodromal and residual symptoms of mood and anxiety disorders, both in research [2] and practice. I had observed that there was a wide interindividual variability of prodromal symptomatology in unipolar depression, bipolar illness, and panic disorder, that is the type, sequence, and duration of symptoms were very heterogeneous. However, there was a strong intra-individual consistency: the same prodromal symptoms that occurred in the first episode were likely to occur in subsequent episodes [2]. I had found, in accordance with literature [2], that the presence of residual symptomatology after treatment was the rule and not the exception. There appeared to be a relationship between residual and prodromal symptomatology according to the rollback phenomenon: as the illness improves, it progressively recapitulates in a reverse order many of the stages and symptoms that were seen during the time it developed [1, 2]. Since prodromal symptoms of relapse tend to mirror those of the initial episode, symptoms occurring both in the prodromal and residual phases deserved special attention [2]. Indeed, residual symptoms were found to be strong predictors of relapse [2]. We felt that there was no room for placing these clinical data in the DSM system [3].

Clinimetrics had provided a conceptual and practical framework for staging in clinical medicine [4]. We thus thought that a clinimetric approach could also be feasible in psychiatry [1]. We developed staging systems for schizophrenia, unipolar depression, mania, and panic disorder with agoraphobia [1]. The model was based on differentiating the prodromal, acute, and residual phases in the first 3 stages, followed by subsequent stage(s) indicating recurrence or chronicity [1]. This staging structure remained substantially the same in subsequent updates [5, 6], where classifications for bipolar disorder, alcohol use disorder, anorexia nervosa, and bulimia nervosa were added [5]. Staging was thus based on the longitudinal development of disorders and their progression in terms of severity and complications [1, 5, 6]. Yet, in clinical medicine staging may also have prognostic, preventive, and therapeutic connotations [4] and such applications were subsequently developed in psychiatry [5].

I will describe the practical use of staging in psychiatry, drawing from the available literature as well as from my very extensive personal experience. I will discuss staging in relation to the clinical state of a person along the continuum of the course of illness, its application to the general population for preventive efforts, and its function for assessing treatment response. I will illustrate how staging requires a clinimetric approach that is in striking contrast with clinical assumptions based on psychometric theory [7].

Robert Kellner and I conceived the process of staging essentially as a retrospective procedure that could be accomplished once a diagnosis of a mental disorder had been made [1]. An insight that we gained from studying prodromal symptomatology in anxiety and mood disorders was that optimal recollection of symptoms could occur only after the acute symptoms had abated upon treatment [2], in line with the methodology that had been introduced by Paykel et al. [8] in life event research. In fact, if patients are questioned about events or symptoms during the acute phase of illness, their recollection may be impaired and they tend to distort their meaning and magnitude [2, 8]. The residual phase appeared to be the most suitable period for exploring what happened in the prodromal phase of illness. The hidden conceptual model of DSM-III [3] was psychometric: all symptoms have the same weight and severity is determined by the number of symptoms, not by their intensity or quality or duration, to the same extent that a score in a self-rating scale depends on the number of symptoms that are scored as positive [7]. In clinimetrics, major and minor symptoms can be differentiated (e.g., diagnostic criteria for rheumatic fever) [9] and the evaluation of symptomatology is not based on number of symptoms, but on their overall impact on the individual [7]. By careful clinical interviewing, facilitated by sensitive clinimetric scales such as Paykel’s Clinical Interview for Depression [10], one could differentiate between major symptoms (occurring in both prodromal and residual phases, potentially developing into prodromal symptoms of relapse) and minor symptoms (occurring only in one phase).

In the staging system that was developed for unipolar depression [1], the specification of a residual phase was particularly important. It paved the ground for the introduction of the sequential model for treating depression that consists in the consecutive application of two forms of treatment: psychotherapy after pharmacotherapy, pharmacotherapy after psychotherapy, sequential use of two psychotherapeutic or pharmacological strategies [7]. It is an intensive, two-stage approach, which derives from the awareness that one course of treatment (whether pharmacotherapy or psychotherapy) is unlikely to entail solution to the affective disturbances of patients. The first application of psychotherapy to the residual stage of depressive illness after pharmacotherapy [11] was subsequently replicated by 16 randomized controlled trials and it resulted in significant long-term benefits in terms of relapse rate [12]. Psychotherapeutic approaches [13, 14] and medications [15] could then be applied according to the stage of development of a disorder. Therapeutic targets were not predetermined but depended on the response of patients to the first course of treatment (e.g., presence of anxiety, impairment of social functioning, persistent sense of fatigue). The strategies, whether psychotherapeutic or pharmacological, could be chosen on the basis of the residual target and not as a predefined option. This was a characteristic of most of the studies on the sequential approach that involved individual therapy [12]. Attention to the longitudinal development of symptoms could also lead to a re-definition of disturbances. For instance, fatigue as a residual symptoms of depression was found to be highly prevalent in patients with a diagnosis of chronic fatigue syndrome, with important therapeutic indications [16].

The staging system based on retrospective individual evaluation upon remission may also be of considerable value when multiple disorders occur. In psychiatry, comorbidity has only a diagnostic connotation and very seldom comorbid diagnoses undergo hierarchical organization (e.g., generalized anxiety disorder and major depression) [3]. When Feinstein introduced the concept of comorbidity in 1970 [17], he referred to having disorders unrelated to the one of interest and to any “additional co-existing ailment” separate from the primary disease, even in the case this secondary phenomenon does not qualify as a disease per se. Indeed, in clinical medicine the many methods that are available for measuring comorbidity are not limited to disease entities [18]. When prodromal symptoms that are not directly related to the main diagnosis of the patient are found, they should be evaluated according to a clinimetric approach, regardless of the diagnostic threshold required by DSM-5 [19], as a source of comorbidity [20]. The staging method provides room for the primary/secondary distinction of mental disorders (e.g., an episode of depression is defined as secondary when it was superimposed on a preexisting psychiatric or medical disease) [21], a simple, but essential, differentiation commonly used in medicine (e.g., hypertension).

The implementation of the retrospective application of staging [1, 5, 6] in patients with a diagnosed mental disorders can be performed in any clinical setting. It requires at least one full assessment of the patient after initial treatment of the acute episode (with particular reference to prodromal and residual symptoms), in addition to the initial evaluation, that should be viewed as always tentative [7]. Diagnostic end-points (DSM diagnoses) are replaced by conceptualization of disorders as “transfer stations,” which are amenable to longitudinal verification and modification. Therapeutic targets are not predetermined by the initial diagnosis but depend on the position of the patient in the staging classification and/or response to a course of treatment. The model is realistic, based on the findings concerned with the longitudinal course of clinical and subclinical symptomatology, and in line with the chronicity and comorbidities of mental disorders [22].

In 2006, McGorry and associates [23] suggested the importance of staging for preventing or delaying progression of mental illness, with particular reference to psychotic disorders and bipolar illness. The targets that ensue from stages may yield intervention strategies also in the early phase of a mental disorder, and not simply after a diagnosis had been made. McGorry et al. [23] adapted the numerical progression we had outlined in 1993 [1] by adding stage 0 (defined as at-risk or latent) to stage 1 (prodromes), 2 (first episode), 3 (single or multiple recurrences), and 4 (chronicity). Such strategy could allow to identify individuals with a prospective instead of retrospective procedure, with considerable implications for early intervention for preventing stage transition [23]. The residual phase despite positive response to treatment that for us applied to the majority of patients (stage 3), in the model by McGorry et al. [23] was substituted by relapse or recurrence. This type of staging retained its basic structure in subsequent formulations [24, 25]. Intervention strategies based on this staging classification and aimed to preventing stage transition in young people, however, yielded modest results [26]. Indeed, the application of stage 0 or 1 to the general population appears to be difficult. The literature that is available [1, 2, 27] indicates the lack of specificity and great interindividual variability of prodromes (stage 1) among individuals with various mental disorders, including schizophrenia. Identifying stage 0 in the general population is even more challenging, in view of the high prevalence of psychiatric symptoms in the general population and the fact that mental illness often occurs in the setting of a preexisting psychiatric disorder, what Robins and Guze [21] defined as secondary forms of affective disorder. For instance, since there are so many roads that can lead to depression [28], it is rather problematic to expect that a specific intervention on a unified pathway (stage 0 or 1) may yield satisfactory results. Unfortunately, the model is idealistic and not realistic, and the feasibility of setting a stage 0 is questionable.

Individual trajectories may also apply to neurobiological correlates in the course of illness [2, 24, 27]. Staging calls for a reassessment of basic pathophysiological models of pathogenesis of mental disorders that neglect intermediate phenomenological steps in the balance between health and disease [2]. The potential utility of biomarkers for setting a stage in mental disorders has been advocated, and yet, also in this case, the results have been modest [23‒25, 27]. The pathophysiological model that is entailed by the existence of a prodromal phase [2, 27] is in line with the concept of allostatic load (the cost of chronic exposure to fluctuating or heightened physiologic responses resulting from repeated or chronic stress) in the balance between health and disease [29]. When environmental challenges exceed the individual ability to cope, allostatic overload ensues. The determination of allostatic load initially relied exclusively on measurements of biomarkers, but it was then expanded to clinimetric criteria [29]. Allostatic load may cause a transition from one stage to another and trigger enhanced vulnerability to relapse. For instance, stressful life events have been associated with onset of depression in conjunction with prodromal symptomatology [27] and relapse during maintenance treatment with antidepressant drugs in the residual phase [30]. A staging system for allostatic load based on clinimetric criteria is available [29]. It is conceivable it may be more suitable for preventive purposes than stages based on illness course.

In addition to allostatic load, euthymia (a trans-diagnostic construct characterized by lack of mood disturbances; presence of positive affect; balance of psychological well-being dimensions, flexibility, consistency, and resistance to stress) may also modulate stages in either a direction of resilience or increased vulnerability [31]. The concept of euthymia means achieving flexibility of the response capacity of the individual in dealing with allostatic load and its biological underpinning [29, 31]. Euthymia is associated with modifications in brain circuits that mobilize resources and govern anticipatory behavior [31]. Dysthymia is conceptualized at the other end of the spectrum and not as a synonym of persistent depression [31]. It is in line with the traditional configuration of neurotic syndrome where people lack the characteristics that allow to cope with environmental changes [32]. Dysthymia is characterized by persistent demoralization, chronic worrying and mental pain, subjective incompetence, rigidity, and abnormal reactivity to environmental stimuli [31]. Between euthymia and dysthymia, there is an intermediate area, defined by Bech as “discomfort” [33], characterized by lack of positive affect without manifestations of distress [31]. Both euthymia and dysthymia can be measured and may demarcate major prognostic and therapeutic differences in vulnerability and stage transition among patients who otherwise seem to be deceptively similar since they share the same psychiatric diagnosis and treatment [31]. A psychotherapeutic strategy geared to pursuing euthymia, Well-Being Therapy (WBT), has been found to prevent stage progression in recurrent depression and to yield beneficial changes in school settings [34].

Recently, Schnyder outlined how the field of psychotraumatology needs to consider the relationships among stress, individual vulnerabilities and strengths (euthymia), longitudinal course of symptoms, response to treatment, and residual symptomatology within a comprehensive staging framework [35]. As a result, a model that is simply based on symptom development is likely to display considerable limitations in its application to the general population for preventive purposes.

In 1995, Thase and Rush formulated a configuration of staging in depression based on prior treatment response, ranging from the situation where an individual did not have a single adequate trial of medication (stage 0) to various forms of nonresponse, from one adequate trial (stage 1) to multiple trials also involving augmentation strategies and electroconvulsive therapy (stages 2–5) [36]. Nonresponse was defined as insufficient decrease in the score of a depression rating scale [36]. The classification retained its basic structure in subsequent proposals concerned with treatment-resistant depression (TRD), even though there were some differences in their formulations [6, 37]. This definition of TRD substantially consists in failure to respond to two or more antidepressant medications trials, despite adequate modalities and adherence [37]. The application of these diagnostic criteria by the Food and Drug Administration and the European Medicines Agency sparked the development of investigational interventions specifically geared to TRD, such as ketamine and esketamine, in addition to switching and combination of therapies [37]. Acknowledged limitation of current definitions of TRD is failure to consider psychotherapeutic interventions [37], despite their recognized efficacy in treating depression, also when it is refractory to medications [38]. Three additional questions, however, are unaddressed.

A first problem is concerned with the definition of adequacy of the interventions. Nierenberg and Amsterdam [39] introduced the term “pseudo-resistance” in depression, for indicating the presence of inappropriate dose and duration of treatment, poor adherence by the patient, important comorbidity that may affect response. However, we should not confound the appropriateness of an intervention that can be evaluated with relatively simple methods against precise standards – and indeed a clinimetric index is available for medications [40] – with its adequacy in a specific clinical situation. Correct use of an antidepressant medication in the first episode of a major depressive disorder may be regarded as appropriate; but is it still adequate in a case of double depression (major depression episodes superimposed on persistent depressive disorder)? The two clinical situations belong to different stages [6] and imply different levels of responsiveness, which is likely to play a particularly important role when comorbidities occur [41, 42]. For instance, anxious depression was found to be less likely to respond to antidepressant drugs compared to non-anxious depression [43]. In a patient with a symptomatology characterized by anxiety and depression of mild severity, we can shift into the domain of resistance what is simply the result of a treatment that has limited efficacy. Poor responsiveness to antidepressants is also a characteristic of symptomatic affective disorders that occur in a restricted number of medical diseases, where mood disturbances tend to subside with medical treatment (for instance, lowering of cortisol level in Cushing’s syndrome) and relapse when such therapy is withheld [44].

Another major problem lies in the failure, if not refusal, of considering iatrogenic factors in resistance to antidepressant drugs [37]. Resistance to re-challenge, loss of clinical effects, paradoxical reactions, switching to hypomania, withdrawal and post-withdrawal syndromes tend to impair responsiveness and may share a common mechanism that has been subsumed under the rubric of oppositional model of tolerance [41, 45]. It is like as if treatment resistance in infectious diseases was conceptualized independently of previous use of antibiotics [41].

Finally, most of current attention on TRD is concentrated on the characteristics of the patient populations and not on the process related to the intervention. How a person experiences the treatment process, his/her interaction with the physician and significant others, the role of the patient in collaborating with therapeutic plan (self-management), are all integral components of therapy viewed as a total human response. Treatment outcome, in turn, is the cumulative result of the interaction of several classes of variables with a selected treatment: living conditions (e.g., housing, nutrition, work environment, social support), patient characteristics (e.g., age, sex, genetic, general health conditions, personality, well-being), illness features and previous therapeutic experience, self-management, and treatment setting (e.g., physician’s attitude and attention, illness behavior) [41]. Such variables may be therapeutic or counter-therapeutic. In certain patients, their interactive combination may lead to clinical improvement, whereas in other cases it may produce no effect or worsening of the condition.

As a result, the basic flaws of current approaches to TRD [37] are to assume that, after testing a standard treatment in a group of patients, we are left with a fairly homogeneous group characterized by resistance, to view improvement as a unitary phenomenon, and to disregard iatrogenic and psychosocial factors. Treatment resistance thus calls for switching and augmentation, instead of reconsideration of the process in treatment selection. The patient is prescribed an increasing number of medications that in the long run may make the illness refractory [41, 45]. When iatrogenic factors are misinterpreted or simply ignored, a cascade of events leading to illness deterioration or its chronic course may result. Simply transferring the indications that emerge from the literature on TRD to practice is likely to lead to unproductive clinical management, unless a number of intermediate evaluations are performed in the individual case. It is simply astonishing how basic clinical issues that need to be addressed in practice are neglected by current literature on TRD [37].

The clinical evaluation of treatment nonresponse in my clinical practice is far more complex than it is assumed [37, 42]. Without clinical reasoning about the potential reasons for failure to respond in an individual case of depression, the current indications for TRD may end up being only a commercial operation for marketing medications or approaches that would never survive the test of time for treating depression in the first place. When I evaluate a case of alleged TRD I start from nonresponse to the most recent treatment a patient has received and I defer the use of the term “resistance” to a later point in more selected cases. I have found that a global evaluation scale (more than an observer scale with different items and a total score) offers a good way to begin with, in line with the high sensitivity of global judgments in randomized controlled trials [7, 20]. Kellner’s global rating scale for changes since the beginning of treatment [46, 47] is a simple clinimetric index with a score ranging from 1 (a lot better) to 3 (better) to 5 (no change) to 7 (worse) to 9 (a lot worse), and the possibility of intermediate scores. Its strong point is that it includes both improvement and deterioration induced by a specific therapy (deterioration may be frequently associated with iatrogenic causes and should be differentiated from nonresponse) [41, 45]. It is then important to evaluate the expected outcome of the intervention that was chosen according to the staging of clinical state of the individual patient [1, 5, 6]. A specific treatment (e.g., antidepressant medication) is likely to yield only partial recovery in relation to the complexity of symptomatology. For instance, when depression ensues after a long-standing anxiety disorder it is wishful thinking to hope that a course of antidepressant therapy is going to entail solution to the preexisting disturbances [43]. Checking the appropriateness of the intervention (the correct use of a therapeutic tool, such as dosage and duration of treatment) completes this initial assessment [40].

The following step is to compare the outcome of the current episode with previous ones. Were there similar instances? Did non-response/deterioration occur in all instances or only in part of them? What differentiates episodes? These basic questions call for further evaluation that extends over several lines of inquiry. The first is concerned with the exploration of potential contribution of iatrogenic factors that may encompass medical [44] and psychotropic [41, 45] drugs, as well as psychotherapy. A staging system for behavioral toxicity of medications has been developed [41, 45] and may assist the physician in identifying specific iatrogenic manifestations. The term “resistance” may find its applicability here. A particularly common form of resistance occurs when a drug which resulted in clinical response in previous episodes is no longer effective when it is started again after a drug-free period [41, 45]. Resistance may also ensue with loss of clinical effect in a patient who previously responded to antidepressant drug treatment [41, 45]. Other clinical manifestations related to behavioral toxicity are withdrawal syndromes and persistent post-withdrawal disorders [41, 45]. In all these cases, pharmacological manipulations, either by switching or augmentation, triggered by a rushed and superficial definition of resistance, may propel depressive illness into a refractory phase, characterized by low remission, high relapse, and high intolerance [41, 45], as it happened in the STAR*D trial [48].

Psychosocial factors in nonresponse and resistance generally find little room in assessment [37, 42] and yet they may yield important lines of clinical interpretation. One line is provided by the concept of allostatic load that may extend to work, unemployment, adverse living conditions, social and educational experiences, income inequality, and the physiological consequences of the resulting health damaging-behaviors, such as poor sleep and diet, smoking, alcohol consumption, and social isolation [29, 49‒51]. Higher allostatic load is associated with poorer health outcomes in both general and clinical populations and may impair treatment response. In clinical practice, it is a common observation that, when patients have some form of allostatic overload (whether at work or in the family or both), the clinical state is unlikely to change unless they develop an alternative way of coping, which pertains more to lifestyle medicine than conventional psychiatry [52].

Another psychosocial line of clinical interpretation is concerned with attitudes to treatment in their experiential, cognitive, and behavioral aspects [53]. For instance, one can observe that certain types of patients seem to antagonize psychotropic drug effects, whether this is due to psychological reactance (a motivational force that leads individuals to fear loss of control), or the balance between internal and external health control beliefs, or to maladaptive illness behavior [53, 54]. Such paradoxical clinical phenomena do not invariably occur in every patient with certain characteristics because they depend on the interaction between patient and doctor. Health attitudes and behavior may be responsive to psychotherapeutic management (application of psychological understanding to the management and rehabilitation of the individual patient, including establishing a therapeutic relationship, identifying current problems with specific assessment procedures, and encouraging self-therapy) which should not be confused with formal psychotherapy [53]. In double-blind placebo controlled trials in psychopharmacology, physician attitudes were found to affect the differentiation between active drug and placebo [55]. Treatment expectations may also influence outcome. If a new treatment is presented as breakthrough cure, its failure sets the stage for the onset of demoralization, a feeling state characterized by subjective incompetence, discouragement, helplessness, and hopelessness [56]. Patients may interpret unfulfilled expectations about therapy as an indication that their condition is untreatable, and such conviction may be reinforced if they perceive disillusionment and frustration in the clinician. As a patient once shared with me referring to a previous treatment experience: “looking at the physician expression, I realized that he had not more to offer to me and my situation was hopeless.” Unfortunately, major clinical phenomena that may ensue in the clinical process are excluded by the reductionistic thinking that characterizes current conceptualizations of treatment resistance.

Staging is a clinimetric procedure [4, 20] that provides an essential complement to the flat, cross-sectional definitions of disorders in DSM-5 [19]. The retrospective staging of the course of illness according to a longitudinal perspective may be applied to everyday psychiatry and clinical psychology. Its effective use, however, very much depends on the quality of clinical data that are collected [57] and on the use of other clinimetric strategies [20]. It requires careful clinical interviewing, the neglected basic method of psychiatry [58, 59]; assessment that is not limited to traditional psychiatric symptomatology, but extends to the evaluation of key psychosocial issues [60], such as allostatic load [29], health attitudes [53, 54], and demoralization [56]; use of repeated evaluations that may modify the initial one [7, 22]; the organization of problematic areas, life setting, and disorders in therapeutic plans that provide a shift from the disease model as a therapeutic target to the attainment of personal goals that can be identified in a specific stage [7, 22].

Staging may play an important role also in setting preventive strategies in the general population or in evaluating treatment responses. However, in these clinical settings the phenomena are more complex and require staging procedures that are not limited to symptoms (e.g., depression, panic) but are extended to relevant issues such as allostatic load [29, 61‒63] and behavioral toxicity [41, 45].

Giovanni A. Fava has no financial conflicts of interest to declare.

Giovanni A. Fava has no funding to declare.

Giovanni A. Fava conceived and wrote the entire manuscript.

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