In recent years, there has been increasing attention to the transdiagnostic approach in psychiatry, particularly in the field of anxiety disorders. The term may refer to psychological constructs, such as low self-esteem and rumination, that are observed across a range of disorders [1]. Alternatively, transdiagnostic models of anxiety consider the similarities among diagnoses to outweigh their differences and contribute to their development and maintenance [2]. Finally, while the classification of psychiatric disorders has led to the development and refinement of diagnosis-specific psychotherapeutic strategies, transdiagnostic approaches are designed to be applicable to patients experiencing a wide range of disturbances and to address comorbidity in a more effective way [1, 3]. Recent examples are a unified protocol to modify neuroticism [4] and an Internet transdiagnostic psychological intervention to promote adjustment to chronic health conditions [5].

These transdiagnostic initiatives attempt to overcome the shortcomings of current classification systems, but are unlikely to entail solution to the clinical problems they intend to address. Indeed, simply broadening the targets of an undifferentiated treatment package seems to run counter the specification of the clinical profile that seasoned clinicians place so much weight upon. It may thus be advantageous to outline the clinical inadequacies that practice of psychiatry restricted to diagnostic criteria implies, how these limitations can be overcome, and how such an approach can be operationalized.

The introduction of diagnostic criteria for the identification of psychiatric syndromes with the third edition the Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1980 [6] considerably decreased the variance due to different assessors and the use of inferential criteria rather than direct observation. Since then, in most instances of diagnostic reasoning in psychiatry, the process ends with the identification of a disorder, often subsumed under a rubric of the DSM. A single assessment generates the prognostic indications and therapeutic choices of the clinician. A DSM diagnosis, however, encompasses a wide range of manifestations, comorbidity, seriousness, prognosis, and responses to treatment, and when two or more diagnoses overlap, as it happens in the majority of cases, substantial problems arise [7].

A neglected key issue has to do with the definition of comorbidity in DSM-III [6] and subsequent editions. When Feinstein introduced the concept of comorbidity in 1970 [8], 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 [9]. In psychiatry, comorbidity has only a diagnostic connotation and important clinical characteristics (e.g., psychological well-being, illness behavior) are unnoticed [7]. Very seldom comorbid diagnoses undergo hierarchical organization (e.g., generalized anxiety disorder and major depression). Regrettably, the DSM-III (6) opted for a flat, cross-sectional view of disorders, ignoring the longitudinal development of mental illnesses. The primary/secondary distinction of disorders (e.g., an episode of depression is defined as secondary when it was superimposed on a pre-existing psychiatric or medical disease) was an important way of providing indications for organizing comorbidity [10], yet even this simple differentiation, commonly used in medicine (e.g., hypertension), was not employed.

Alvan Feinstein’s [8] classic definition of comorbidity also referred to antecedent pathological events that were judged to affect the current disease process. The cross-sectional nature of the classification systems in psychiatry has limited the use of the term “comorbidity” to what a patient may be currently experiencing. The concept of iatrogenic comorbidity refers to the unfavorable modifications in the course, characteristics, and responsiveness to treatment of an illness that may be related to previously administered therapies [11]. Such vulnerabilities may manifest themselves during treatment administration and/or after its discontinuation. Current diagnostic methods in psychiatry based on DSM refer to patients who are drug free and do not take the issue of iatrogenic comorbidity into consideration. They are suited for a patient who no longer exists: most of the psychiatric cases that are seen in clinical practice today receive some forms of psychotropic drug treatment [11].

An additional problem of DSM [6] and subsequent editions lies in the construction of items of diagnostic criteria. The hidden conceptual model is psychometric: 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 depression self-rating scale depends on the number of symptoms that are scored as positive [12]. In clinical medicine, major and minor symptoms can be differentiated (e.g., diagnostic criteria for rheumatic fever) [13].

Finally, while the DSM-III included an axis on psychosocial and environmental problems that might affect the diagnosis, treatment, and prognosis of mental disorders [6], its most recent edition (DSM-5) deleted any reference to the role of stress and social factors [14]. As a result, the standard, current diagnostic classification system in psychiatry refers to “nowhere patients” [15], omitting their personal history (including previous treatments) and crucial psychosocial factors that make the individual vulnerable to disease and resilient when disease occurs [16].

Clinimetrics, the science of clinical measurements, is a domain concerned with indices, rating scales, and other expressions that are used to describe or measure symptoms, physical signs, and other clinical phenomena which do not find room in the customary taxonomy [13, 17]. Taxonomy, in fact, does not include patterns of symptoms, severity of illness, effects of comorbid conditions, timing of phenomena, rate of progression of illness, functional capacity, and other clinical features that demarcate major prognostic and therapeutic differences among patients who otherwise seem deceptively similar because they have the same diagnosis and laboratory results [13, 17]. There are five main implications of the clinimetric approach to the clinical process in psychiatry [7].

Building Unitary Concepts

A unique feature of the clinimetric approach is to provide a broad global rating of clinical phenomena [13, 17]. It may take the form of a global evaluation of the overall severity of comorbidity by means of an index, such as Charlson Comorbidity Index [18]. Or it may bring together clinical manifestations that would otherwise be scattered. Tyrer and associates [19] remarked that what is shared by syndromes such as anxiety, panic, phobic disturbances, and irritability may be as important as the differences between them and conditions that are apparently comorbid could be part of the same clinical syndrome. They argued that the combination of mixed anxiety and depressive disorders together with a certain type of abnormal personality (excessive timidity, poor self-esteem, avoidance of anxiety provoking situations, and dependence on others) constitutes a single syndrome, the general neurotic syndrome [19]. Unfortunately, over the years the concept of neurosis has assumed a negative and derogatory connotation (let us just think of the term “neurotic”) which makes its current use questionable. For this reason, Per Bech and I [20] revisited Eysenck’s definition of dysthymia [21] to indicate neuroticism. The term “dysthymia” may sound confusing, since it had been used in DSM-III [6] to indicate chronic depression, yet in DSM-5 [14] it was replaced by “persistent depressive disorder.” A current definition of “dysthymia” [22] encompasses distinct and yet ostensibly related manifestations: liability to demoralization, chronic worrying, and mental pain; subjective incompetence (the perception of being uncertain, inadequate, and indecisive in dealing with situations); rigidity; and abnormal reactivity to environmental stimuli (the tendency to respond to various situations with intense negative emotions). Recognition of the features of dysthymia, regardless of the presenting psychiatric disorder, indicates that a therapeutic approach directed only to the current symptomatology is unlikely to entail solution to the clinical situation of the patient.

Building unitary concepts is not simply a matter of recognizing the common ground of certain psychological manifestations. It is also finding for certain symptoms a context that is more meaningful than what is provided by diagnostic criteria of a specific disorder. The concept of euthymia [20, 22] constitutes an example of such process. Euthymia is a construct characterized by lack of mood disturbances; presence of positive affect (e.g., cheerfulness, ability to relax); balance of psychological well-being dimensions, flexibility, consistency, and resistance to stress [20, 22]. Euthymia may provide a framework for a renewed definition of recovery, for measuring treatment outcome and for targeting interventions [22]. Promoting euthymia may also improve flexibility of the individual response capacity, which may entail long-lasting remission from psychiatric disorders and more successful and enduring results in lifestyle medicine [22].

Another important application of setting clinical manifestations in a broader context is allostatic load (the cost of chronic exposure to fluctuating or heightened neural and systemic physiologic responses, possibly exceeding the coping resources of an individual) [23, 24]. The concept of allostatic load provides a synthesis of the cumulative effects of experiences in daily life that involve chronic stress, life events, as well as work experience, unemployment, adverse living conditions, social and educational experiences, and income inequality throughout life span [23, 24]. This comprehensive model also included the physiological consequences of the resulting health-damaging behaviors, including poor sleep and other aspects of circadian disruption, unhealthy diet, smoking, alcohol and drug consumption [23, 24]. When environmental challenges exceed the individual ability to cope, then allostatic overload ensues, with major negative health consequences [24, 25]. Diagnostic criteria for the identification of allostatic overload have been developed and validated by a large body of studies [24, 25]. Criteria encompass symptoms such as restless sleep, lack of energy, irritability, and demoralization, and significant impairments in social or occupational functioning and in environmental mastery (feeling overwhelmed by the demands of everyday life) [24-26].

A final and increasingly important example of building unitary concepts can be subsumed under the rubric of behavioral toxicity [27]. In 1968, Di Mascio and associates introduced this term referred to the pharmacological actions of a drug that, within the dose range in which it has been found to possess clinical utility, may produce alterations in mood, perceptual, cognitive, and psychomotor functions that limit the capacity of the individual or constitute a hazard to his/her well-being [28]. For instance, as to antidepressant drugs it may include manifestations such as loss of clinical effects during long-term treatment; paradoxical reactions; switching to a hypomanic or manic state; withdrawal syndromes upon tapering and/or discontinuing medications; persistent post-withdrawal disturbances; resistance when a drug that was successfully used in the past is reinstituted; refractoriness to new medications [11, 27, 29]. It warns the clinician to a state of iatrogenic comorbidity [11], that may suggest refraining from further use of antidepressants and pursuing alternative strategies, such as psychotherapy. The concept of behavioral toxicity may also apply to food consumption as a form of addiction [30].

Expanding the Assessment of Comorbidities

Exclusive reliance on diagnostic criteria has restricted assessment to a limited number of symptoms, omitting consideration of the psychosocial environment of the individual (allostatic load), subclinical symptoms, psychological well-being, illness behavior, and lifestyle. A number of clinimetric interviews are available and may supplement those geared to diagnostic criteria. The Diagnostic Criteria for Psychosomatic Research (DCPR) may help identifying allostatic overload, demoralization, irritable mood, and various manifestations of illness behavior [22, 31, 32]. The Clinical Interview for Dysthymia and the Clinical Interview for Euthymia are also available [22]. Clinimetric tools for assessing lifestyle and related variables, such as alcohol consumption, nicotine dependence, and sleep problems, may also be used [33].

Staging and the Longitudinal Development of Symptoms

The staging method to describe the longitudinal development of mental disorders was introduced in 1993 [34], with a considerable delay compared to other medical disciplines. The model for unipolar depression included 5 stages: prodromal phase, acute major depressive episode, residual phase, dysthymia/recurrent major depression, and chronic major depressive episode [34]. This classification retained its basic structure in subsequent proposals [35]. Staging may be based on the longitudinal development of disorders, its progression in terms of severity and complications, or response to treatment. It defines where a person currently is along the continuum of the course of illness. For instance, according to the DSM-5 cross-sectional perspective [14], certain symptoms may not reach the diagnostic threshold of a disorder and be discarded as of minor value. Yet, with staging the same symptoms can be interpreted as residual after a course of treatment and may constitute a considerable risk for relapse [35]. Staging is thus uniquely geared to identifying individual trajectories. It provides room for the primary/secondary distinction, regardless of the diagnostic threshold required by DSM-5 [35]. There appears to be a relationship between residual and prodromal symptomatology according to the rollback phenomenon: as the illness remits, it progressively recapitulates, even though in a reverse order, many of the stages and symptoms that were seen during the time it developed [36]. Since prodromal symptoms of relapse tend to mirror those of the initial episode, symptoms occurring in both the prodromal and residual phases deserve special attention [36].

Clinimetric Differentiation of Symptoms

In classical psychometrics, all items of a rating scale have the same weight and measure parallel forms of the same symptom [12]. The misleading effects of the psychometric model become particularly evident using psychiatric diagnostic criteria [7]. The clinimetric approach allows a discrimination of symptoms according to a number of variables: intensity; their duration and trajectory (e.g., residual symptoms that occurred also in the prodromal phase of illness); and their individual impact on the patient (certain symptoms may be more threatening or invalidating). Targum and associates [37] have developed specific criteria (SAFER) to be used in drug trials for increasing the assessment accuracy of symptoms (e.g., symptoms are present primarily during episodes of acute illness and not steadily present throughout the person’s life; symptoms impact multiple domains and contexts, such as school, work, home, and social relations). The clinimetric differentiation between major and minor symptoms [7] allows to overcome artificial psychometric configurations, such as the categorical/dimensional and the state/trait dichotomies.

Repeated Assessments

Another important aspect of the clinimetric approach has to do with the need of repeated assessments. Psychiatrists and clinical psychologists have come to believe that a single assessment, regardless of the phase of illness, may be sufficient to reach the diagnostic target and may generate therapeutic decisions that get prolonged for years. There is evidence to call such view in question [7]. For instance, an adequate appraisal of prodromal symptomatology is likely to occur only when the patient has recovered [36]. Feinstein [38] remarks that, when making a diagnosis, thoughtful clinicians seldom leap from a clinical manifestation to a diagnostic endpoint. The clinical reasoning goes through a series of “transfer stations,” where potential connections between presenting symptoms and pathophysiological process are drawn. These stations are a pause for verification or change to another direction [38].

A reassessment that is close to the initial evaluation may bring some important data, such as the stability of symptoms detected and the opportunity of monitoring the lifestyle of the patient through a diary [39]. A post-treatment evaluation may disclose areas that were left untouched, emerging aspects that had been neglected, and vulnerabilities triggered by treatment. Follow-up assessments may yield additional valuable insights.

The development of clinimetrics had the purpose to maintain and improve clinical art while advancing the state of clinical sciences [13]. A clinimetric approach may help expanding the narrow range of information that is currently used in psychiatry based on diagnostic criteria. It is uniquely geared to the individual patient and to the interaction between patient and physician. It is in sharp contrast with approaches that purport generalized solutions for organizing comorbidities based on cumbersome psychometric and statistical procedures.

Emmelkamp et al. [40] introduced the use of macro-analysis and micro-analysis in the functional assessment preceding cognitive-behavior therapy. Macro-analysis may include complaints that are not part of diagnostic criteria, but are perceived by the clinician to be important. A relationship between co-occurring syndromes and problems is established on the basis of where treatment should commence in the first place. Micro-analysis is a detailed analysis of specific symptoms or syndromes (e.g., onset and course of the complaints, circumstances that worsen symptoms and consequences) [40]. For instance, when anxiety characterizes the clinical picture, it is necessary to know under which circumstances anxiety becomes manifest, what does the patient when he/she becomes anxious, whether an avoidant behavior occurs, and what are the long-term consequences of the avoidant behavior [40].

This assessment strategy was subsequently expanded to become a general psychiatric or psychosomatic evaluation [7, 17, 20, 22, 29, 41], within the clinimetric formulation. Macro-analysis is based on the main elements and problematic areas that are collected during the interview. Their inclusion is consistent with the medical concept of comorbidity [7-9] and is thus not limited to the presence of psychiatric disorders or medical diagnoses. Macro-analysis selects problematic areas (e.g., frequent discussions with spouse), functional impairments, stressful environmental circumstances, illness behavior, use of medications, and health-damaging lifestyle. It is not limited to negative aspects of functioning, but may also include some areas related to euthymia that stand despite the presence of distress [22, 39], thus providing a picture of the balance between strengths and weaknesses of the individual patient. All these elements are simply collected on a sheet of paper. Macro-analysis provides a ground for formulating hypotheses that may have an explanatory power, may group scattered syndromes under a unifying umbrella, and suggest therapeutic plans. The ability of clinicians to develop alternative diagnostic hypotheses from the beginning of their inquiry has been found to be a distinctive feature of expert clinicians with a high rate of diagnostic accuracy [42]. Macro-analysis not only is a tool for the therapist, but can also be used to inform the patient about the relationship between different problem areas and motivate the patient for changing. The clinician’s view of the problem can be shared with the patient, with opportunities for additions and modifications. It paves the ground for subsequent shared decisions as to the therapeutic processes, a method that is still seldom practiced in psychiatry [7]. The components of macro-analysis lend themselves to hierarchical organization that is based on the personal history of the patient (biography) and his/her perceptions, preferences, and priorities.

Macro-analysis cannot always be completed after a standard clinical evaluation, because some elements may be missing. For instance, important information as to the type of medication and the duration of treatment may not be remembered by the patient. Or the patient has not brought medical documentation that may shed some light on his/her conditions. As a result, a second assessment evaluation needs to be scheduled. We should keep in mind, however, that macro-analysis is always tentative (transfer station) and needs to be updated and verified in subsequent encounters. For instance, in sequential treatment of mood disorders a full assessment is required before therapy, after the first course of treatment, after the second course of treatment, and at follow-up [43]. Each time, it identifies the targets of treatment.

Several examples of macro-analysis have been published in journal articles [7, 17, 20, 22, 39, 44] and books [29, 45, 46] in brief clinical vignettes. However, it may worth outlining a couple of more detailed case descriptions here.

Isabel is a 48-year-old secretary, married, with two children. She presents with fatigue, irritability, and low mood, associated with generalized anxiety and sleep difficulties. She does not fulfil DSM-5 criteria for a specific mood or anxiety disorder [14] and has no previous history of psychiatric disturbances. Her complaints fall into the rubric of anxious depression [44]. As such, she would be a very good candidate to get a “life sentence” with antidepressant medications: antidepressants would be very unlikely to yield a satisfactory effect due to the predictable poor response of anxious depression [44]; such failure would trigger further pharmacological attempts, associated with side effects and vulnerabilities, in a cascade iatrogenesis [11]. The problem is that the exclusive use of DSM-5 [14] is clearly insufficient. When I explored the life setting of Isabel and tried to understand how and why certain symptoms appeared, I found out that a couple of years before her mother fell ill and needed a lot of support. Isabel did her best trying to reconcile caregiving, work, and family, but with limited success and very little help from her relatives (particularly her sisters). Sleep became more and more restless, and she woke up in the morning already feeling tired. Generalized anxiety and restless sleep with ensuing fatigue in the morning were identified as major symptoms. In Figure 1, we indicate her major symptoms as two of her problematic areas. Two other areas were the protracted stress of caregiving and frictions with her sisters (Fig. 1). Isabel’s condition appeared to be consistent with allostatic overload [24, 25]. I shared my appraisal of the situation with the patient, and I explained the strong links among the symptoms that she suffered from. I stated that, in my opinion, there was no solution unless she tried to lessen her allostatic burden. I suggested some changes in her daily schedule and a reduction in caregiving, more in line with lifestyle medicine [47] than psychiatry. I added that the suggested changes might improve some of her interpersonal frictions. These suggestions were written on the prescription pad as if they were a medication. I also prescribed a benzodiazepine (clonazepam at low doses) for improving certain symptoms, particularly sleep and anxiety (Fig. 1). I decided to see the patient again in a month to check about the implementation of the suggested lifestyle changes and about her coping with some unavoidable guilt that the fact of decreasing the time she spent with her mother might have caused. Isabel complied with my prescriptions, and when I saw her again, she was already doing much better. In due course, I discontinued clonazepam with no problems.

Fig. 1.

Macro-analysis of major symptoms and problematic areas.

Fig. 1.

Macro-analysis of major symptoms and problematic areas.

Close modal

In this example, it appears that setting certain symptoms related to sleep, anxiety, and mood in the context of allostatic overload provides incremental information to the clinician and potential directions for management. The following example clarifies the importance of attributing the symptomatology of the patient to different causes and to place treatment interventions in a sequential way.

Richard is a 28-year-old married accountant who presented with an obsessive-compulsive disorder that was treated by his primary care physician with sertraline 50 mg/day. The initial effects were good, but in a matter of months improvements faded and did not respond to dose augmentation. His physician thus switched him to venlafaxine (first 75 mg/day, then 150 mg/day), with modest results. In the transition phase between tapering sertraline and starting venlafaxine, he suffered from a withdrawal reaction, with symptoms that lasted months. In the meanwhile, he also developed mild depressed mood, characterized by deep apathy never experienced before. I formulated the hypothesis of a state of behavioral toxicity associated with antidepressants, on the basis of loss of clinical effects and withdrawal symptomatology that became a persistent post-withdrawal disorder with sertraline and paradoxical effects (depression and apathy) related to venlafaxine (Fig. 2). Obsessive-compulsive symptomatology predated the use of antidepressants and could not be attributed to behavioral toxicity. These symptoms created considerable problems to Richard both at work and in the family. I shared my assessment with him, and I suggested we should give priority to treatment of obsessive-compulsive disorder by cognitive-behavior therapy. I also expressed my opinion that venlafaxine had to be discontinued, but I warned Richard that this was not going to be easy, also based on a staging system of phenomena linked to behavioral toxicity [29]. We thus opted for starting cognitive-behavior therapy as soon as possible, postponing the intervention to remove venlafaxine at some later point in time (Fig. 2), according to a sequential model [29].

Fig. 2.

Macro-analysis of syndromes and iatrogenic comorbidity.

Fig. 2.

Macro-analysis of syndromes and iatrogenic comorbidity.

Close modal

The case suggests that it is wishful thinking to believe that one of course of treatment, no matter how generalized and articulated, would entail solution to the problems presented by most patients we currently see. We may need two or more courses of treatment, according to a sequential model, where each step is dictated by a specific assessment [7].

Macro-analysis generally needs to be supplemented by micro-analysis. Micro-analysis may consist of additional clinical interviewing, to clarify specific areas that are deemed to be important (e.g., obsessive-compulsive and depressive symptomatology in the case of Richard). Clinimetric instruments, such as Paykel’s Clinical Interview for Depression [48], may allow to rate intensity, quality, and features of symptoms. Clinimetric tools for unitary concepts (e.g., the Clinical Interview for Euthymia, the Clinical Interview for Dysthymia, the DCPR Semi-Structured Interview) may also be used [22]. Finally, micro-analysis may focus on patient-reported outcome measures [49] that are likely to reflect the patient’s evaluation of affective symptoms, stress, lifestyle, well-being, illness behavior, and mental pain [41, 50].

After the introduction of DSM-III [6], the illusion of simplicity has characterized the clinical process in psychiatry and clinical psychology. Assessment was mainly restricted to the identification of DSM disorders, omitting a large part of the patient’s distress, problematic areas, and biography. Clinicians have very limited tools for addressing and organizing comorbidities in the majority of their patients, who do not qualify for one, but for several disorders. Diagnostic criteria were automatically translated into treatment targets. As it took place in other areas of medicine [51], any new treatment, with special reference to those supported by the pharmaceutical industry, was heralded as a breakthrough cure of a psychiatric disorder, setting the stage for disillusionment and frustration of the clinician when the test of time provided a more realistic appraisal of the therapeutic tool. The availability of treatments drove assessment to the “discovery” or “rediscovery” of disorders [52], in a process that is just opposite to finding solutions to the clinical needs that emerge from practice [53].

Psychiatrists are generally aware of the limitations linked to the use of diagnostic criteria and ensuing treatment strategies. They are often frustrated by their limited success with the disorders they treat and by the chronicity of disturbances of their patients. In this climate, it is appealing to believe that genetics and neurosciences, in due course, are going to transform and improve practice. Precision medicine, the genomics-based knowledge that may lead to tailoring of treatment to the biological individual characteristics of each patient [51], may thus solve also the problems of psychiatry. Unfortunately, reliance on the genetic make-up of the individual is generally based on the assumption of a fixed condition over the lifetime, whereas everything changes, both as a result of the natural course of the disease and its interactions with treatments [25, 29]. Biomarkers are considered to be the stairway to precision psychiatry, but may be affected by various causes, not necessarily reflecting a disease process [54].

Psychiatrists may wait for this type of precision psychiatry. Nothing has really come up in the past decades, as exemplified by the fields of psychiatric genetics [55] and functional neuroimaging [56], but we may be really close. In the meanwhile, diagnostic criteria may be integrated with clinimetrics to capture the personal attributes and the environment of each individual, as well as the evolutions of disturbances over time, yielding a different model of personalized psychiatry. Use of clinimetric strategies may lead to unique individual profiles that take into account both biology and biography, and lend themselves to the use of clinical judgment [57]. It may be an antidote to oversimplified models that derive from biological reductionism, neglect individual responses to treatment, and clash with clinical reality [53, 57].

The author has no conflicts of interest to declare.

The author has no funding to declare.

The author conceived and wrote the entire manuscript.

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