Scott and associates [1] have performed a systematic review of the studies on trajectories of depression and anxiety in chronic medical diseases. By means of meta-analytic procedures they found that most patients (69% for depression and 73% for anxiety) displayed a stable and low trajectory of distress. There was a smaller percentage of patients (11% for depression and 14% for anxiety) who had high levels of distress that tended to persist over time [1]. There were also patients who reported increasing or decreasing trajectories of psychological symptoms. The nature or severity of medical disease did not appear to meaningfully affect outcomes [1]. The instruments that were used in the studies were very heterogeneous and mainly involved self-rating scales. The results of the study should be interpreted in the context of high heterogeneity and an aggregate data approach (e.g., the contribution of specific treatments, such as antidepressant medications, could not be ascertained). Nonetheless, the importance of identifying patients who poorly adjust to chronic medical illness or suffer from relatively independent psychological distress is highlighted [1]. In particular, depression may influence how a person experiences the pathological process and interaction with others (including medical staff), affects outcome, and hinders medical care [2].

But how do we identify a depressive state in the medically ill? The fact that a patient fulfills DSM-5 diagnostic criteria [3] may seem to be helpful in setting a threshold for conditions worthy of clinical attention. However, several of the symptoms required for the diagnosis of a major depressive disorder (e.g., fatigue, sleep, or appetite disturbances) may be present regardless of whether the patient is actually depressed [2, 4]. Simply counting the number of symptoms and using diagnostic criteria as a checklist may thus be misleading in a medical setting. The hidden conceptual model is psychometric: severity is determined by the number of symptoms, not by their intensity or quality [5]. We may infer the presence of a mood disorder by using the cut-off point of a self-rating scale. The problem is, however, the same: a score in a depression self-rating scale depends on the number of symptoms that are scored as positive [5]. Further, the lack of opportunities for clarification through clinical interviewing may increase the likelihood of spurious findings.

The evaluation of depression in the setting of medical disease is a difficult task that requires consideration of several clinical variables. A clinimetric approach [6] may help overcoming the limitations of DSM-5 [3]. The clinimetric perspective provides an intellectual home for the reproduction and standardization of the clinical intuitions. It allows the clinician to make full use of the clinical information that is available. Exclusive reliance on diagnostic criteria has impoverished the clinical process and does not reflect the complex thinking that underlies decisions in psychiatric practice [6].

In DSM-5 [3], assessment is mainly restricted to the identification of major depressive episodes or persistent depressive disorders, omitting a large part of the patient’s distress, problematic areas, and biography [6]. There is an increasing amount of research that points to the importance of demoralization in the medically ill, a feeling state characterized by the patient’s consciousness of having failed to meet his/her own expectations (or those of others) or being unable to cope with some pressing problems [7]. Subjective incompetence, discouragement, helplessness, and hopelessness are the clinical hallmark of the syndrome. Both diagnostic criteria and a clinimetric rating scale (the Clinical Interview for Demoralization) are available [7]. This expansion of the targets of clinical evaluation should be associated with a careful qualitative appraisal of symptoms and the differential diagnosis with those that are part of the symptomatology of medical disorders. The clinimetric approach allows a discrimination of symptoms according to a number of variables: intensity; duration and trajectory; and impact on the patient (indeed, certain symptoms may be more invalidating). For instance, fatigue is probably the most prevalent symptom of illness, whether physical or mental [8], and can hardly be attributed to a depressive disorder with any reasonable certainty. However, depressed patients tend to feel most fatigued when they get up in the morning and gradually improve as the day goes on, while the reverse sequence is the rule when physical factors are responsible [8]. When chronic fatigue is the chief, unexplained, medical complaint, it may be a residual symptom of a previous episode of depression [9]. The trajectory of the symptoms, as the review of Scott and associates underscores [1], is another key element in evaluation. In a classic study [10], Moffic and Paykel followed on a weekly basis 43 medical inpatients found to be depressed on admission until discharge. In 11 out of the 43 patients (28%), depression completely resolved by the time of discharge. Most were patients in whom mood showed a dramatic improvement concomitant with recovery from a life-threatening illness [10]. The findings suggest the importance of monitoring the trajectory of depressed mood during hospitalization. In a recent study [11], a total of 288 patients with a first episode of acute coronary syndrome underwent semi-structured interviews for DSM-IV mood disorders [12] and DCPR demoralization [7]. The interviews were performed before discharge to minimize the contaminating effects of hospitalization. There were 43% of cases of demoralization and only 3% of major depressive disorder [11].

Another crucial clinimetric step is to relate symptomatology to the evolution and features of medical disturbances over time, together with individual characteristics and environmental factors. There are medical disorders for which there is evidence in the literature for resolution of the mood disturbance with specific treatment for the organic disease (for instance, lowering of cortisol level in Cushing’s syndrome) and relapse when treatment is withheld [2]. In these cases, a specific organic factor, on the basis of brain pathology (e.g., stroke) or neurotransmitter balance, is judged to be etiologically related to the mood disturbance. In DSM-5 [3], these disorders are subsumed under the poorly specified diagnosis of depressive disorder due to another medical condition. The term “symptomatic affective disorder” [13], that also includes depression ensuing from use of drugs related to medical conditions [14], is more clinically meaningful. Criteria for differentiating symptomatic affective disorders from other mood disturbances in the setting of medical disease are available [2]. An important aspect is that symptomatic affective disorders are unlikely to respond to antidepressant medications, regardless of the severity of their manifestations [2, 13].

It has repeatedly been shown that clinically significant depression is not an inevitable concomitant of serious medical disability and is not related to the severity of physical illness [1, 2, 13]. The course and vicissitudes of a medical disorder, including convalescence and rehabilitation, are filtered by the individual’s past experiences, current life circumstances, and future aspirations [15]. Interlocking processes at neurophysiological, biochemical, and experiential levels, including the burden of treatment and the expectations that may arise, may constitute themselves a form of allostatic load, the cost of chronic exposure to fluctuating or heightened physiologic responses, in addition to environmental circumstances characterized by repeated or chronic stress [16]. There is a close relationship between allostatic load, demoralization, depressive disorders, and vulnerability to illness [16]. This means that a careful exploration of patient’s psychiatric symptomatology needs to be associated with medical history that includes previous patient-doctor interactions, as well as individual health attitudes and behavior [17]. Listening to the patient’s beliefs on the illness and its treatment, with an open-ended style of interviewing, may verify whether a doctor has provided an adequate appraisal of the situation, with opportunity for discussion and clarification, and identify inadequate expectations and convictions that may yield demoralization and depression. For instance, we evaluated the case of a middle-age man who reacted to an initial diagnosis of mild type-2 diabetes with gloom and deep discouragement. He viewed the diagnosis, on the basis of what happened to a relative, as a life sentence that would have led him to develop insulin-dependent diabetes and medical complications very rapidly. When we challenged his view, illustrated how lifestyle medicine could improve or even reverse his disorder, and encouraged him to discuss his situation with his primary care physician, demoralization faded. In this case, illness perceptions yielded mood disturbances. However, in many cases, the reverse is true: depression and demoralization may affect health attitudes and behavior, shaping lifestyle, presentation of symptoms, access to patient care, interactions between patients and physicians, adherence to medical advice, response to treatment [17].

Once symptoms of depression and demoralization have been placed in the individual context and personal history of the patient (with particular reference to characteristics of medical illness, medications, allostatic load, patient-doctor interaction, and health attitudes and behavior), a complex picture is likely to emerge. It is thus wishful thinking to believe that acting on a single component by prescription of antidepressants or psychotherapy may be sufficient for a clinically meaningful impact. Not surprisingly, both pharmacotherapy and psychotherapy, when properly used, may, at best, address mood disturbances but are unlikely to have an impact on medical outcomes [2, 18]. Indeed, a sequence of clinical steps is recommended.

A first clinical task is that of evaluating the potential role of iatrogenic factors. The impact of medications with depression as an adverse effect may be considerable [19], and yet it tends to be systematically neglected, also because physicians are unlikely to think in iatrogenic terms [20]. Table 1 lists the most consistent associations between medical drugs and the occurrence of depression. A careful phenomenological appraisal of drug-related depression disclosed the prevalence of a mixture of lethargy, apathy, tiredness, and drowsiness, at times accompanied by confusion, more than the specific features of a major depressive disorder [21]. However, at times suicidal ideations may be present, even without the context of a severe depressive symptomatology [2, 13, 14, 21]. Discontinuing the medication or substituting it with another of the same therapeutic class may improve the clinical situation [2, 13, 14, 21]. Certain medications (e.g., fenfluramine, finasteride) are likely to induce depression after their discontinuation, as withdrawal or persistent post-withdrawal disorders [20, 22]. The same phenomenon is likely to occur with antidepressant medications [20, 22]. One should thus keep in mind that behavioral toxicity may also derive from the use of psychotropic drugs that a patient may already be taking, an event that is increasingly common with the widespread use of antidepressants [22]. Iatrogenic determinants, however, are not limited to medications and interventions, but may also encompass patient-doctor interactions [15]. For instance, the current tendency to induce excessive hopes and limitless expectations about therapies [23] may lead to demoralization when miracles then do not happen, particularly in patients who have a long history of treatment failures [7].

Table 1.

Medical drugs that have consistently been associated with depression [2, 13, 14, 19‒22]

Baclofen 
Cimetidine 
Cycloserin 
Efavirenz 
Fenfluramine 
Finasteride 
Flunarizine 
Interferon 
GnRH antagonists 
Levetiracetam 
Levodopa 
Methyldopa 
Oral contraceptives 
Propranolol 
Ranitidine 
Reserpine 
Steroid hormones 
Sulfonamides 
Tamoxifen 
Tiagabine 
Topiramate 
Vigabatrin 
Baclofen 
Cimetidine 
Cycloserin 
Efavirenz 
Fenfluramine 
Finasteride 
Flunarizine 
Interferon 
GnRH antagonists 
Levetiracetam 
Levodopa 
Methyldopa 
Oral contraceptives 
Propranolol 
Ranitidine 
Reserpine 
Steroid hormones 
Sulfonamides 
Tamoxifen 
Tiagabine 
Topiramate 
Vigabatrin 

A subsequent clinical task is to evaluate the role of the medical illness in producing a symptomatic affective disorder [2, 13]. The most consistent associations are reported in Table 2. In these disorders, the trajectories of psychiatric symptoms tend to follow the patterns of medical disturbances. For instance, in Cushing’s syndrome depressive symptoms tend to subside with lowering of cortisol levels, while they are unlikely to respond to antidepressant medications. In both cases of symptomatic affective disorders (medications and illnesses), risk factors are history of depression and psychosocial stressors [2, 13, 14, 20, 21]. The identification of a symptomatic affective disorder should not lead to the assumption of finding “the cause,” but it is only an element of a multifactorial clinical presentation.

Table 2.

Medical disorders that have consistently been associated with symptomatic affective disorders [2, 13]

Endocrine diseases: Cushing’s syndrome, Addison’s disease, primary aldosteronism, hypothyroidism, hyperthyroidism, hyperparathyroidism, hyperprolactinemia 
Neurological diseases: Parkinson’s disease, cerebrovascular disorders, Huntington’s chorea, Alzheimer’s disease, cerebral tumors, multiple sclerosis, head injury, normal pressure hydrocephalus 
Infectious diseases: hepatitis, mononucleosis, AIDS, COVID, encephalitis 
Carcinoma of pancreas, lung cancer 
Systematic lupus erythematosus 
Folate deficiency, pernicious anemia 
Endocrine diseases: Cushing’s syndrome, Addison’s disease, primary aldosteronism, hypothyroidism, hyperthyroidism, hyperparathyroidism, hyperprolactinemia 
Neurological diseases: Parkinson’s disease, cerebrovascular disorders, Huntington’s chorea, Alzheimer’s disease, cerebral tumors, multiple sclerosis, head injury, normal pressure hydrocephalus 
Infectious diseases: hepatitis, mononucleosis, AIDS, COVID, encephalitis 
Carcinoma of pancreas, lung cancer 
Systematic lupus erythematosus 
Folate deficiency, pernicious anemia 

Finding a common ground for certain psychological manifestations would be the next logical step. Even though a major depressive episode and demoralization may coexist, in many cases they may occur independently and the two syndromes are not connected by a hierarchical relationship (i.e., depressed patient may not suffer from demoralization and demoralized patients may lack the symptoms of a major depressive disorder) [7]. Indeed, demoralization, as defined by the Diagnostic Criteria for Psychosomatic Research (DCPR) [24], consists of very specific symptoms, is unlikely to respond to antidepressant medications, may benefit from psychotherapy but also, because of its strong link with allostatic load, from lifestyle medicine [7]. In the DCPR, hopelessness (when the individual feels he/she alone is responsible for the situation and there is nothing he/she or anyone else can due to overcome the problem) can be indicated as an important clinical specifier for demoralization [24]. The diagnosis of major depressive disorder sets the clinical threshold for the forms of depression that are likely to respond to antidepressant medications [13]. However, in medical settings an informed, clinimetric use of diagnostic criteria, based on severity and implications of symptoms in terms of quality of life, health attitudes, and disability, is warranted [6]. The diagnosis may thus be feasible in a patient who presents with only two or three severe symptoms that entail consequences on health attitudes and behavior and may not be indicated in a patient who barely meets 5 or 6 criteria [5, 6].

The presence of allostatic overload, maladaptive illness behavior, impaired psychological well-being, poor self-management, and adherence, in addition to depression and/or demoralization, may call for the use of specific psychotherapeutic strategies. Illness and medication beliefs derive from cognitive schemas (i.e., enduring, negative, and distorted representations that affect how individuals perceive themselves and the world around them) [17]. Cognitive-behavior therapy has been found to be effective in modifying illness-related negative schemas and dispositions [17]. Recently, attention has been called to schemas that hinder euthymia [25] that is characterized by the presence of positive affect and psychological well-being; the balance and integration of psychic forces (flexibility); a unifying outlook on life which guides actions and feelings for shaping the future accordingly (consistency), and resistance to stress (resilience). Unlike previous models related to psychological well-being, which are exclusively focused on the intraindividual level, euthymia results from interacting mechanisms at the individual, interpersonal, and environmental levels [25].

In conclusion, use of clinimetric strategies in the clinical evaluation of depression and/or demoralization associated with medical disease may lead to unique individual profiles that take into account both biology and biography (life experience) and lend themselves to the use of clinical judgment [6]. It 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, that may lead to more satisfactory and enduring results than current therapeutic strategies. Addressing any expression of sadness, demoralization, or depressed mood with a prescription of antidepressant drugs under the poorly specified and misleading rubric of depression is an unjustified practice that is likely to lead to major iatrogenic damages, particularly if protracted over time [20, 22]. It is also a practice that makes psychiatric and psychosomatic consultations of little value (any nonpsychiatric physician can do the same) and neglects the skills of psychiatrists and psychologists, who use sophisticated forms of clinical judgment, master techniques of interviewing and history taking, and are geared to capture the iatrogenic components of psychopathology. In the setting of medical disease, a comprehensive assessment is likely to yield incremental care, by use of distinct and yet ostensibly converging lines of therapeutic action.

Giovanni A. Fava and Jenny Guidi have no conflicts of interest to declare.

Giovanni A. Fava and Jenny Guidi have no funding to declare.

Giovanni A. Fava and Jenny Guidi conceived and wrote the entire manuscript.

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