Differential Diagnosis in Disorders with Depressive Symptoms: Exact Clinical Framing and Proposal of the “Perrotta Depressive Symptoms Assessment”

Giulio Perrotta; Stefano Eleuteri; Irene Petruccelli

doi:10.3390/psychiatryint6030073

,

and

Faculty of Psychology, Universitas Mercatorum, Piazza Mattei 10, 00186 Rome, Italy

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Author to whom correspondence should be addressed.

Psychiatry Int.2025, 6(3), 73;https://doi.org/10.3390/psychiatryint6030073

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Abstract

Introduction: In the literature, depression is a medical condition that is well known and has been studied for decades, yet in clinical practice it often happens that depressive symptoms are confused with structured disorders or complexes. This incorrect interpretation can lead the psychiatrist to choose to make a psychopharmacological prescription, relegating psychotherapy to mere support or in any case reducing its importance, risking making the patient’s symptoms chronic and overloading the healthcare system. Materials and Methods: The literature up to December 2024 was reviewed and 40 articles were included in the review. A pilot study was conducted to verify the effectiveness and validation of the proposed theoretical model. Results: We propose the use of the “Perrotta Depressive Symptoms Assessment” (PDSYA) for the differential diagnosis in disorders with the manifestation of depressive symptoms, to facilitate the correct diagnosis and to reduce interpretative errors, both at a nosographic and therapeutic level. Conclusions: In the pilot study, in the content validity analysis, all items obtained a CVR score greater than the cut-off value, with a minimum score of 0.811. Therefore, all items of the scale were considered essential; also, regarding the relevance of the items in exploring the constructs investigated, optimal values of I-CVI (>0.93) and scale (S-CVI > 0.98) were obtained. Therefore, all items were rated as relevant. The validation study of the model is underway with a representative sample.

Keywords:

depressive; depressive disorder; depressive symptoms; depressive personality disorders; mood; bipolar; psychotic disorder; anxiety; anxiety disorder

1. Introduction

1.1. General and Clinical Profiles

In the literature, depression is a medical condition that has been well known and studied for decades, with a precise nosographic framing based on symptoms [1]. In particular, the Diagnostic and Statistical Manual of Mental Disorders, version 5—rev (DSM-5-TR) uses the term “depression” to refer to one of the depressive disorders described in the manual [2]. Based on symptoms (depressed mood for most of the day, marked decrease or loss of interest or pleasure in new or enjoyed activities, psychomotor agitation or slowing down, fatigability, loss or lack of energy/life impetus, physical prostration, anxiety and sleep disorders, significant weight loss without dieting, or significant weight gain, or decreased or increased appetite, psychosomatic disorders and tendency to isolation, loneliness, sedentariness, poor self-care and self-abandonment with decreased social and emotional relationships, suicidality and hopelessness/pessimism), it is possible to identify other forms of depression, such as dysthymic disorder or those with specificity or without [2,3]. Symptoms of depressive spectrum disorders are often comorbid with other mood disorders, such as bipolar disorder [3,4], but they are always related to specific dysfunctional personality patterns [5,6].

Epidemiological estimates consider depressive disorder to be among the highest in incidence in the population, settling it between 5% and 8% of the general population and 15–35% of the psychiatric population, especially in the adult and mature segments [7,8,9].

The etiology of depressive disorders is not yet known, but both genetic and environmental factors contribute to the symptomatology [10]. Heredity determines about half of the etiology (less so in late-onset depression) [11]. Depression is therefore more common among first-degree relatives of depressed patients, and concordance among identical twins is high [12,13]. Other hypotheses point instead to changes in neurotransmitter levels, including abnormal regulation of cholinergic, catecholaminergic (noradrenergic or dopaminergic) glutamatergic, and serotonergic (5-hydroxytryptamine) transmission [14,15,16]. Neuroendocrine dysregulation may be a factor, with particular emphasis on the three axes: hypothalamus–pituitary–adrenal, hypothalamus–pituitary–thyroid, and growth hormone–hypothalamus–pituitary. However, it is not yet clear in the literature whether neurotransmitter alterations are necessarily the cause of depressive spectrum disorders or whether they are the consequence of them [17,18,19]. Psychosocial factors, such as work stress and the social reference environment, also seem to be involved [20,21]. Severe existential stresses, particularly separations and losses, generally precede episodes of major depression; however, such events usually do not cause major depression except in individuals predisposed to a mood disorder, and in any case, less resilient and/or anxiety-prone individuals are more likely to develop a depressive disorder [22,23]. The female sex presents a higher risk of suffering from depressive symptoms (net of common causes such as traumatic episodes, negative experiences, and work stress), especially in adulthood and mature age probably due to an etiology combined with the hormonal profile, but in the literature there is not yet a clear position on this profile [24]. Certain drugs, such as corticosteroids, some beta-blockers, interferon, and reserpine, can cause depressive disorders. The abuse of certain substances and illicit substances (e.g., alcohol, amphetamines) can trigger or accompany depression. Toxic effects or withdrawal from substances can cause transient depressive symptoms [25].

The importance of an accurate clinical framework in the manifestations of the depressive spectrum arises from the need to correctly frame the morbid condition to decide on the best clinical approach (whether psychotherapeutic, psychopharmacological or combined) [26,27,28,29,30]. In clinical practice it often happens that depressive symptoms can be misinterpreted and confused with depressive disorders, as they are also present in anxiety disorders, bipolarism, dementia, substance use, and various medical conditions [31,32]. This can happen because the symptomatology is common to several disorders (as it is between bipolar disorder and borderline disorder), but it can also be faked, for personal reasons (to show up sicker, in fictitious disorders or to attract attention) or economic reasons (attainment of a disability pension), even in good faith (in somatizations), and thus the risk of prescribing the wrong drug therapy is very high, thus reducing the importance of psychotherapy or risking chronicizing the patient’s symptoms and overburdening the health care system with unnecessary costs [33,34,35,36].

For this reason, targeted intervention is needed to clarify the boundaries of differential diagnosis, in hypotheses of clinically relevant manifestations with depressive symptoms.

1.2. Objectives

A review was conducted to determine the clinical boundaries of depressive symptoms to aid exact diagnosis and reduce the risk of diagnostic error, both in terms of nosographic framing and treatment. The objective of this discussion is to try to determine whether, in the current state of scientific knowledge, the following research questions can be answered:

(1): Can the difference between depressive symptoms and depressive disorders be determined?
(2): Can a new scale of severity of depressive manifestation be determined with *reasonable* certainty that can fill the current gap in the literature?
(3): Can we propose a model that helps to correctly frame the patient’s clinical condition when *he/she/they present(s) with* depressive symptoms?

2. Materials and Methods

2.1. Study Design and Review Questions

Literature was reviewed on Pubmed. To identify the salient aspects, the author focused on the elements that can determine the exact differential diagnosis of disorders presenting with depressive symptoms.

2.2. Materials and Methods

The authors selected systematic reviews, clinical trials, and randomized controlled trials using the keywords “depression disorder” AND “differential diagnosis” and selected 2399 useful results, from January 1971 to December 2024; of these, only 34 were included in the present narrative review paper and concern the last decade of publications. To have a broader and more comprehensive overview of the topic, 6 more publications were selected (in relation to academic manuscripts such as official manuals), for a total of 40 results to enrich the literature present in the introduction. The content of the selected manuscripts did not contribute to the nomenclature and diagnostic criteria of the proposed new model which is instead based on the DSM-5-TR [2] and the Perrotta Integrative Clinical Interviews 3 (PICI-3) [5]. Simple reviews and opinion contributions were excluded because they were not relevant or redundant to this work. The search was limited to English-language articles (Figure 1).

Figure 1. PRISMA flowchart template. Adapted from Matthew J. Page et al., BMJ 2021; 372:n71 [37].

Finally, a pilot study was conducted to verify the effectiveness and validation of the proposed theoretical model, using the method suggested by Kishore et al. [38], based on a power analysis with the outcome indicated in the section relating to the results of the pilot study.

3. Results: “Perrotta Depressive Symptoms Assessment” Proposal

3.1. Can the Difference Between Depressive Symptoms and Depressive Disorder Be Determined?

Yes, it is possible. In literature and clinical practice, the diagnostic criteria are clear and comprehensive with respect to the nosographic figures described. Based on the specific depressive symptoms and their characteristics (duration, intensity, and triggers), the most appropriate diagnostic framing can be determined (Table 1); however, the DSM-5-TR as well as other sources (e.g., the Psychodynamic Diagnostic Manual—PDM-II or International Classification of Diseases 11th Revision—ICD-11) are not yet able to provide a holistic model that can guarantee the therapist the exact diagnostic framing, without risking the interpretation of depressive symptoms necessarily as a disorder present in nosography but simply as dysfunctional personality traits. Therefore, for the purposes of diagnosis and treatment, it is important to have a tool that can support the therapist in clinical operations.

Table 1. DSM-5-TR diagnostic criteria related to principal depressive disorders.

3.2. Can a New Scale of Severity of Depressive Manifestation Be Determined with Reasonable Certainty That Can Fill the Current Gap in Literature?

Currently, no. There are no proposed models in the literature that succeed in determining the degree of functional impairment, except in terms of malaise and distress complained of by the patient. The scale values of the psychometric tests used to diagnose depressive disorder (e.g., the Beck Depression Inventory—BDI, or the Minnesota Multiphasic Personality Inventory 2—MMPI-II) are able to investigate the severity of the condition according to a logic of increasing score (the higher the score the greater the dysfunction found), but there is no model capable of organizing the depressive universe in a holistic and structured manner.

3.3. Can We Propose a Model That Helps to Correctly Frame the Patient’s Clinical Condition When He/She/They Present(s) with Depressive Symptoms?

Based on the critical issues encountered in terms of a psychopathological diagnosis and subsequent treatment, it was decided to structure a theory (Perrotta Depressive Symptoms Assessment Theory, PDSYA-t), a model (Perrotta Depressive Symptoms Assessment Model, PDSYA-m), and a scale (Perrotta Depressive Symptoms Assessment Scale, PDSYA-s), which were able to meet this clinical need, offering the therapist theoretical–practical support to correctly diagnose his patient’s psychopathological condition. Figure 2 shows the diagnostic flowchart for the differential diagnosis of disorders with depressive symptoms according to the proposed model. The Perrotta Depressive Symptoms Assessment is described in detail in the following section.

Figure 2. Diagnostic flow chart for differential diagnosis for disorders with depressive symptoms.

3.4. Perrotta Depressive Symptoms Assessment (PDSYA)

To meet all the corrective needs of the current diagnostic profile of depressive disorders, the “Perrotta Depressive Symptoms Assessment” (PDSYA) is proposed, which has the following technical features (Table 2), among which the model (Table 3) and scale (Table 4) are also defined.

Table 2. Technical characteristics of the “Perrotta Depressive Symptoms Assessment”.

Table 5. Perrotta Depressive Symptom Assessment Scale for Therapies (PDSYA-s-t). “Level” represents the increasing scale of representation of psychopathological severity about depressive symptoms. The “color” is the exact corresponding of the levels, in its graphical representation. The “description” is the column for the descriptive listing of the specific level.

Table 3. Perrotta Depressive Symptoms Assessment Model (PDSYA-m). The “nosographic category” represents the definition of the new nosography. The “type” represents the specific subtype. The “description” is the column for the descriptive listing of the specific level according to the descriptive criteria.

Table 4. Perrotta Depressive Symptom Assessment Scale (PDSYA-s). “Level” represents the increasing scale of representation of psychopathological severity about depressive symptoms. The “color” is the exact corresponding of the levels, in its graphical representation. The “specificity” is the mathematical result of the summation between 2 physical quantities: intensity (I understood as subjective perception of pervasiveness of depressive symptoms) and frequency (f, understood as the number of daily repetitions of depressive symptoms), according to individual subjective values ranging from 1 (low) to 3 (high). The “description” is the column of the descriptive details.

3.5. Pilot Study to Proceed with the Validation of the Model

From the “Perrotta Depressive Symptom Assessment Model” (PDSYA-m) proposal, a questionnaire was designed and developed with the aim of reducing the risk of diagnostic error of depressive symptoms and framing them in a functional manner with respect to one’s structural personality profile, according to the PICI-3 model, for an age range between 12 years and 70 years. It must be administered by the therapist and cannot be self-administered in any of its parts.

To facilitate the process of classifying depressive symptoms, a questionnaire with progressive questions was developed, divided into three sections: the first (A), with 8 items, relating to preliminary personal and clinical data; the second (B), with 9 items, relating to the severity index of the depressive state (ED), using three different sub-indexes (general dichotomous yes/no response, intensity and frequency perceived by the patient); and the third (C), with 18 progressive response items, relating to the diagnostic classification of depressive symptoms, using the general dichotomous yes/no response index.

The study is underway with a representative population sample, but here we proceed to report the research data on a limited population sample, to proceed with a pilot study to demonstrate the validity of the construct [38].

Based on the seven steps to follow for the development of a questionnaire, the validity analysis data based on the pilot study are reported below. The structured questionnaire was subjected to statistical analysis, using a pilot population sample (36 people, aged 18 to 65 years, 18 males and 18 females; M: 41.5, SD: 13.6).

The power of the sample was tested with a statistical analysis that required a population sample of no less than 24 units.

Therefore, the content validity ratio (CVR) measure was used to assess the relevance of the questionnaire, while the content validity index (CVI) measure was used for representativeness and clarity, as suggested by Kishore et al. [38]. The CVR is a statistical method for establishing content validity, while the CVI is the average CVR for all items included in the final instrument. Appropriate S-CVI values are ≥0.80. For qualitative content validation, the same group was asked two open-ended questions (one concerning the items and one about the administrative procedure): 1. “Is the language form adopted in defining the items described clear and understandable?” 2. “Evaluate the clarity and language form adopted to describe the administration procedure”. These questions were analyzed qualitatively using a thematic content analysis approach, taking into consideration any suggestions for clarification of the language form of the items.

It was administered through a clinical interview lasting 30 min for each participant, during November 2024 and February 2025, recording data in a single form, and reused anonymously and in aggregate.

In the case of content validity, all items scored CVR above the cut-off value, with a minimum score of 0.811.

Therefore, all scale items were considered essential. In addition, regarding the items’ relevance in exploring the investigated constructs, optimal I-CVI (>0.93) and scale (S-CVI > 0.98) values were obtained. Therefore, all items were rated as relevant (Table 6).

Table 6. Data collection of PDSYA-Q1, according to the scheme of Kishore et al. [38]. The content of the items is indicated in the following Appendix A.

4. Discussion

In clinical practice, the differences between symptoms, conditions, manifestations, and disorders are often confused by practitioners, and it is not uncommon as revealed by the readings that in psychiatry, identification errors related to diagnosis, and consequently treatment, can be made. In addition, there is a marked tendency in psychiatry to prefer drug therapy as the first level of intervention, instead of adhering to psychotherapy, preventing the patient from cognitively intervening on symptoms to promote change. On the other hand, it is well known that drug therapy intervenes on the symptom by trying to limit it or make it disappear, but it is psychotherapy that teaches the patient what to do and how to change the perceptual state with respect to the problem, then finding the solutions [39,40].

Currently, there are no models that can clarify the diagnostic boundaries in the area of depressive manifestation and reduce the risk of misinterpretation of one or more symptoms (e.g., diagnosing depression in a person with a narcissistic covert personality, who tends to use depressive symptoms to blame and attract attention, reinforcing them if he or she succeeds in achieving what is desired). The PDSA thus seeks to fill these interpretive gaps, offering the following correctives to the current clinical approach:

Allows grading the spectrum of complexity of the depressive manifestation, distinguishing the hypotheses of a depressive condition from that of a depressive disorder, through mixed forms, offering the therapist a flow chart for differential diagnosis and the best type of clinical intervention.
It allows the exact diagnosis of the nosographic category involved in the investigation to be distinguished using specific structural and functional criteria.
Allows early intervention even on the mildest or attenuated forms, to facilitate a gradual psychotherapeutic intervention, without necessarily waiting for the strict nosographic criteria of a depressive disorder to be met. Unlike the DSM-5-TR, this model does not distinguish only in categorical terms but also in functional/ dysfunctional terms.
Allows the severity of depressive manifestation to be graded, based on subjective criteria, in relation to the intensity and frequency of the symptoms themselves.

Systematically defining the differential diagnosis of disorders presenting with depressive symptoms means being able to frame the subject both structurally and functionally, choosing the most appropriate treatment and avoiding letting the therapist decide based on his or her own assumption or subjective interpretation of the patient’s symptomatic experience or only based on the patient’s narrative. It is therefore extremely important to be able to carry out such an operation to give clinical dignity to a clinical manifestation that, to date, has not yet been fully explained and is often diagnosed only in its most severe and disabling forms, chronicizing the patient’s symptomatology and irrational beliefs.

The presence of depressive symptoms cannot simply be traced back to depressive disorders but must be assessed clinically, in the differential diagnosis, to decide on the best diagnosis and treatment most adherent and functional for the patient’s condition. To facilitate the therapist’s work, the Perrotta Depressive Symptom Assessment (PDSYA) tries to reduce the risk of diagnostic error, both in the identification phase of the nosographic condition and in the therapy phase (psychological and pharmacological).

5. Limitations and Future Prospects

This pilot study uses a small but powerful population sample according to the appropriately produced statistical analysis, and this result gives us hope for the outcome of the study that is underway with an adequate and representative population sample. This size currently represents a limitation for the generalization of the results; however, based on the statistical results obtained, we are confident in being able to state that the model has a good chance of being considered valid with the extended study.

In the future, research should focus on the practical requirements of this clinical need, with greater attention to etiological causes, the role of neurotransmitters and neural correlates, the best structural and functional framing of the subject’s personality, and the most appropriate therapy to pursue.

6. Conclusions

The proposal of the new theoretical model of the “Perrotta Depressive Symptoms Assessment”, supported by the questionnaire, has demonstrated in the pilot study a fair content validity considering all the essential and relevant items. The validation study of the model is ongoing with a representative sample, but these results reinforce the hypothesis of its validity being able to generalize its results. This will allow preventive intervention even in attenuated or mild forms of a depressive nature and will allow us to focus on the diagnostic label and therapeutic objectives, reducing the risk of interpretative errors and promoting a better approach and a better resolution of depressive spectrum disorders.

Author Contributions

G.P. is the creator and developer of the theory, model, questionnaire, and scale. He is also the editor of the manuscript. S.E. and I.P. are co-authors and reviewers of the final manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval were waived for this study due to Legislative Decree No. 52/2019 link: https://www.gazzettaufficiale.it/eli/id/2019/06/12/19G00059/sg (accessed on 9 June 2025) and Law No. 3/2018, link: https://www.gazzettaufficiale.it/eli/id/2018/1/31/18G00019/sg (accessed on 9 June 2025).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author due to ethical approval requirements.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

Perrotta Depressive Symptom Assessment (PDSYA). Perrotta Depressive Symptom Assessment Theory (PDSYA-t). Perrotta Depressive Symptom Assessment Model (PDSYA-m). Perrotta Depressive Symptom Assessment Scale (PDSYA-s). Perrotta Depressive Symptom Assessment Scale for Therapies (PDSYA-s-t). Perrotta Depressive Symptom Assessment Questionnaire (PDSYA-Q1). Diagnostic and Statistical Manual of Mental Disorders, version 5—rev (DSM-5-TR). Psychodynamic Diagnostic Manual 2 (PDM-II). International Classification of Diseases 11th Revision (ICD-11). Perrotta Integrative Clinical Interviews 3 (PICI-3). Depressive Disorder (DD). Perrotta Human Emotions Model-2 (PHEM-2).

Appendix A

Table A1. Perrotta Depressive Symptoms Assessment Questionnaire (PDSYA-Q1).

Perrotta Depressive Symptoms Assessment Questionnaire (PDSYA-Q-1)
SECTION A: Preliminary biographical and clinical data
N	Item	Answer
1	Name and surname
2	Date of Birth (Age)
3	Place of birth
4	Habitual domicile
5	Phone/Cel.
6	Email
7	Medical psychophysical history
8	Drug therapies
SECTION B: Depressive State Severity Index (ED)
N	Item		Answer	Intensity—Frequency		Score partial
1	Depressed mood, which consists of external character manifestations in sad, melancholy, passive and negative ways, with respect to circumstances and the socio-environmental context that instead turn out to be positive or in any case neutral, thus risking compromising the functioning of one or more spheres of life (e.g., personal, social, work, affective)
2	Low self-esteem, which consists in having a tendentially negative attitude towards life, believing little in oneself or in one’s own resources, or in any case in one’s abilities and means, due to insecurity, with a tendency to isolation, loneliness, a sedentary lifestyle, poor self-care or self-abandonment with/without a decrease in social and affective relationships (affective symptoms)
3	Marked decrease in pleasure in carrying out new interests and activities (anhedonia) or in any case previously liked or interested, while now they arouse fatigue, apathy, fear of failure, boredom and disinterest
4	Significant increase or decrease in body weight since the onset of the first depressive symptoms, which may result in eating disorders
5	Psychomotor agitation or slowdown, in the absence of manic/hypomanic symptoms and/or marked neurotic symptoms (e.g., phobic, obsessive, somatic), with/without alterations in the sleep–wake rhythm (insomnia or hypersomnia) and in one’s natural biorhythm
6	Perception of lack of energy or easy fatigue (asthenia)
7	Feelings of self-devaluation, restlessness, helplessness, worthlessness, inadequacy, emptiness, guilt, or shame, affecting self-perception and ability to plan
8	Reduced ability to concentrate and/or memory
9	Recurrent negative, melancholic or death-related thoughts that are not provoked by real events (e.g., mourning)
			__/9(Y)
SECTION C: Thematic path for differential diagnosis
N	Item				Answer
1	Is there a perceived dysfunctional mental state, with depressive symptoms? (If the answer is “no” you can interrupt the questionnaire, with the result of “Absence of clinically relevant depressive state” and you can stop the administration, if the answer is “yes” you can continue with no. 2)
2	Is the score in the third column of Section B of the questionnaire at least 5/9? (If the answer is “no” you can continue with no. 3, if the answer is “yes” you must continue with no. 8)
3	Has the respondent recently been exposed to one or more sources of stress to which he or she cannot resolutely adapt, and has he or she developed an abnormal and/or distressing emotional and behavioral response? (If the answer is “no” you can continue with no. 5, if the answer is “yes” you must continue with no. 4)
4	Is the period of difficulty or inability to adapt decisively, to the specific source of stress, lasting less than 30 days? (If the answer is “no” you can continue with no. 5, if the answer is “yes” the diagnosis will be “Adjustment disorder, with depressive symptoms” and you can stop the administration)
5	Is the stressful event to which one cannot adapt decisively perceived by the interviewee as a traumatic event? (If the answer is “no” you can continue with no. 7, if the answer is “yes” you must continue with no. 6)
6	Is the traumatic event capable of generating intrusive thoughts, nightmares, flashbacks, avoidance of trauma memories, negative cognitions and mood, hypervigilance, and sleep disturbances? (If the answer is “no” you can continue with no. 7, if the answer is “yes”, to at least 50% of the requirements listed, the diagnosis is “Post-traumatic stress disorder, with depressive symptoms” and the administration can be stopped, if the answer is “yes” but with less than 50% of the requirements listed, the administration can be continued with no. 7)
7	Does the interviewee manifest, in addition to depressive symptoms, specific neurotic symptoms of an anxious type (panic, phobias, avoidance, obsessions, somatizations) capable of negatively impacting daily life in a significant way? (If the answer is “no” you can continue with no. 8, if the answer is “yes” the diagnosis is “Specific anxiety disorder, with depressive symptoms” and the administration can be stopped)
8	Does the depressive state last less than 30 days? (If the answer is “no” you can continue with no. 12, if the answer is “yes” you can continue with no. 9)
9	Is the depressive state connected to one’s premenstrual/menstrual period? (If the answer is “no” you can continue with no. 10, if the answer is “yes” the diagnosis is “Premenstrual/menstrual dysphoric disorder and the administration can be discontinued)
10	Is the depressive state connected to seasonality or in any case to the weather/? (If the answer is “no” you can continue with no. 11, if the answer is “yes” the diagnosis is “Seasonal dysphoric or meteopathic disorder and the administration can be stopped)
11	Is the depressive state connected to the stressful-traumatic event, despite psychotherapeutic intervention? (If the answer is “no” you can continue with no. 12, if the answer is “yes” the diagnosis is “Complicated adjustment disorder and the administration can be stopped)
12	Is the depressive state only partially able to compromise general mental functioning, with marked perceptions of discomfort and psychophysical malaise, without however preventing him from living his own existence and without excessive impairments (in any case less than 50% of the average quality of life) in the spheres of life? (If the answer is “no” you can continue with no. 13, if the answer is “yes” the diagnosis is “Sub-clinical depressive disorder can be discontinued)
13	Has the depressive state lasted for more than 90 days? (If the answer is “no” the diagnosis is “Atypical depressive disorder and the administration can be stopped, if the answer is “yes” the answer can be continued with no. 14)
14	Is the depressive state present continuously or in any case for more than 75% of the average time of the reference period? (If the answer is “no” the diagnosis is “Atypical depressive disorder and the administration can be stopped, if the answer is “yes” the answer can be continued with no. 15)
15	Has the depressive state lasted for at least 1 year? (If the answer is “no” the diagnosis is “Atypical depressive disorder and the administration can be stopped, if the answer is “yes” the answer can be continued with no. 16)
16	Is the depressive state present continuously or in any case for more than 75% of the average time of the reference period? (If the answer is “no” the diagnosis is “Reactive depressive disorder and the administration can be stopped, if the answer is “yes” the answer can be continued with no. 17)
17	Has the depressive state lasted for at least 2 years? (If the answer is “no” the diagnosis is “Dysthymic depressive disorder and the administration can be stopped, if the answer is “yes” the answer can be continued with no. 18)
18	During the depressive state, are there anxious-humoral symptoms (e.g., panic, phobias, obsessions, avoidance, somatization, hypomanic), dramatic (e.g., manic, grandiose, theatrical, impulsiveness, antisociality, psychopathy) and/or psychotic (e.g., delusions, hallucinations, dissociations, paranoia), in a non-sporadic, non-occasional and disabling way? (If the answer is “no” the diagnosis is “Major depressive disorder” and the administration can be stopped, if the answer is “yes” the diagnosis is “Mixed form depressive disorder” of the anxious-depressive, manic-depressive-dramatic-depressive or psychotic-depressive type, based on the specific symptoms”, and the administration can be stopped)
CLINICAL NOTES

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Figure 1. PRISMA flowchart template. Adapted from Matthew J. Page et al., BMJ 2021; 372:n71 [37].

Figure 2. Diagnostic flow chart for differential diagnosis for disorders with depressive symptoms.

Table 1. DSM-5-TR diagnostic criteria related to principal depressive disorders.

N	Nomenclature	DSM-5-TR Diagnostic Criteria
1	“Major depressive disorder” (or unipolar)	A. Criterion A: ≥5 of the following symptoms must have been present almost every day during the same 2-week period, and one of them must be a depressed mood or loss of interest or pleasure (major depressive episode): depressed mood for most of the day; marked decrease in interest or pleasure in all or almost all activities for most of the day; significant (>5%) weight gain or loss or decrease or increase in appetite; insomnia (often maintenance [central] insomnia) or hypersomnia; psychomotor agitation or slowing observed by others (not self-reported); asthenia or loss of energy; excessive or inappropriate feelings of self-evaluation or guilt; decreased ability to think or concentrate or indecision; recurrent thoughts of death or suicide, a suicide attempt, or a specific plan to carry it out. B. Criterion B: Failure to frame the psychotic sphere (schizophrenic spectrum, delusional disorder, or psychotic disorder not otherwise specified). C. Criterion C: Absence of a manic or hypomanic episode or mixed mood. Specific indicators are related to severity (mild, moderate, severe without psychotic manifestations, severe with psychotic manifestations, in full or partial remission, unspecified), episode (chronic, with catatonic manifestation, melancholic, atypical, postpartum). The presence of 2/+ major depressive episodes within 60 days specifically defines “Recurrent (or Persistent) Major Depressive Disorder”.
2	“Dysthymic disorder”	A. Criterion A: Depressed mood, most of the day, almost every day, for at least 2 years. B. Criterion B: Presence of 2/+ symptoms including poor appetite or hyperphagia, insomnia or hyperinsomnia, low energy or asthenia, low self-esteem, difficulty concentrating or making decisions, feelings of hopelessness. C. Criterion C: Symptoms described in criteria A and B must persist without interruption throughout the two-year period. D. Criterion D: Absence of major depressive episodes throughout the two-year period. E. Criterion E: Absence of manic or hypomanic episodes. F. Criterion F: Illness does not occur exclusively during the course of a psy-chotic disorder. G. Criterion G: Symptoms are not due to substance use. H. Criterion H: Symptoms result in clinically significant distress or impair-ment in social, occupational, or other areas of functioning. Specific indicators are related to episode (early, late) and manifestations (with or without atypicality).
3	“Depressive disorder not otherwise specified”	Includes disorders with depressive manifestations that do not meet criteria (e.g., premenstrual dysphoric disorder, minor depressive disorder, brief recurrent depressive disorder, post-psychotic, depressive disorder superimposed on a psychosis).
4	“Prolonged grief”	Prolonged grief is the persistent sadness that follows the loss of a loved one. It differs from depression in that the sadness relates to the specific loss rather than the more general feelings of failure associated with depression. Unlike normal grief, this condition can be highly disabling and requires therapy specifically designed for prolonged grief disorder. For the diagnosis of prolonged grief, the bereavement response (characterized by persistent longing or desire and/or concern for the deceased) lasts a year or more and is persistent, pervasive, and above cultural norms. It must also be accompanied by ≥3 of the following conditions during the past month to an extent that causes distress or disability: feeling of identity disruption (e.g., feeling that a part of oneself has died); marked disbelief about death; avoidance of what reminds one of the loss; intense emotional pain related to the death; difficulty engaging in ongoing life; emotional numbness; feeling of insignificance; intense loneliness.

Table 2. Technical characteristics of the “Perrotta Depressive Symptoms Assessment”.

Perrotta Depressive Symptoms Assessment
Theory (PDSYA-t)	The current clinical setting of a depressive disorder leaves too much room for interpretive error at the diagnostic stage, with the negative consequence of an incorrect prescription in terms of treatment. The diagnostic criteria of the DSM-5-TR are clear and concise, but they do not represent the whole depressive universe in a structured way, and this facilitates interpretive error. Therefore, a new model is needed that can combine the best of the current clinical literature into a systematic assessment framework to be offered to the therapist, with narrow margins for interpretation, to reduce the risk of diagnostic error.
Model PDSYA-m)	The Perrotta Depressive Symptoms Assessment allows the subjective profile of the depressed individual to be evaluated if all criteria of both the structural and functional diagnoses are met (Table 3), allowing the therapist to interpret the individual’s subjective experience in a more comprehensible way, reducing the risk of interpretive errors. The model is described in the diagnostic flowchart (Figure 2) and is structured into 3 levels and 4 types, which describe in their entirety the depressive manifestation. The structural and functional model of personality is taken from the Perrotta Integrative Clinical Interviews 3 (PICI-3) [5], which frames depressive disorder as a personality disorder. In PDSYA-m, depressive disorders and typical mixed forms are always personality disorders, while more attenuated forms (such as depressive conditions and atypical mixed forms) are instead mood disorders associated with a specific personality picture that may not necessarily be a depressive disorder. Unlike the DSM-5-TR, this model uses criteria divided according to structure and functioning, with a flow chart to include or exclude the diagnosis. Also, unlike the DSM-5-TR, in this model the time limits of symptom manifestation vary.
Scale (PDSYA-s)	The Perrotta Depressive Symptoms Assessment is structured in intensity and frequency values, with each level defining the precise condition of clinical interest. Specific condition severity markers are provided, which more closely define the negative impact of the clinical condition, in addition to 9 different colors according to the symptom’s severity (Table 4). Each nosographic category (depressive conditions, depressive disorder, and mixed forms) has its own scaling, meaning that each type of depressive manifestation can be rated by the patient on a scale of 0 to 3 for both intensity and frequency, as the rating is subjective and depends solely on the perceptual state of the person experiencing depression. “Specific markers (or characterizers) of severity” are considered those circumstances, specifically, that feed the depressive symptom by hyperactivating it, promoting or actually maintaining the depressive decompensation: reinforcements from the social-environmental context (e.g., dysfunctional family conduct), the prolongation of the negative effects of the traumatic event from which the depressive reaction originated (e.g., the bereavement), the tendency to feed the emotional states resulting from the distressing mode (e.g., reserved and passive nature), and personal (e.g., attention-seeking), social (prolongation of the period of social estrangement) or economic (e.g., receipt of disability or retirement benefits) advantage in feeding the depressive state. These markers help define, with the therapist, the level of severity of intensity and frequency used in the PDSA-s. Coupled with the PDSA-s is the clinical intervention scale, to help the therapist frame the best possible intervention based on the severity of the symptomatology (PDSA-s-t), (Table 5).

Table 3. Perrotta Depressive Symptoms Assessment Model (PDSYA-m). The “nosographic category” represents the definition of the new nosography. The “type” represents the specific subtype. The “description” is the column for the descriptive listing of the specific level according to the descriptive criteria.

Perrotta Depressive Symptoms Assessment Model (PDSYA-m)
Nosographic Category (Depressive Manifestations)	Type	Description
“Depressive conditions”	Subclinical depression	These are conditions of potential clinical interest, where the patient manifests depressive symptoms but in a milder or less impactful form than depressive disorders (e.g., premenstrual dysphoria, occasional seasonal dysphoria, adjustment deficit, short depressive episode, less than 30 days). Thus, they have a limited negative impact on the patient’s life, such that their overall functioning is not impaired but sufficient for them to perceive psychological and physical distress and discomfort. Psychological evaluation is suggested.
“Depressive disorders”	Reactive (or situational) depression	STRUCTURAL DIAGNOSIS. This is a nonhabitual, stable, pervasive but not persistent pattern (mood disorder), characterized by depressed mood, low self-esteem, and marked decrease in interests and pleasures, from 3 to 12 months, due to a specific event that generated the distressing state (stems from an adjustment disorder that has been active and unreworked for at least 30 days, e.g., events during pregnancy, separation stressors or hypercontrol in postpartum, postpartum, prolonged seasonal dysphoria, persistent bereavement with depressive symptoms for less than 1 year, maladjustment to the traumatic event). Manic/hypomanic and/or psychotic symptoms are not present. The depressive state is thus a reaction to the specific triggering event, leading the subject to react with emotional closure in response to the stressor source. If unmanaged and reworked, it leads to chronicity; therefore, psychotherapy support is highly recommended, but without drug therapy, except for restraint and in the most severe and structured cases. If it persists for more than 1 year, it becomes dysthymic disorder. FUNCTIONAL DIAGNOSIS. There must be at least 5 of the following 9 clinical criteria of major depressive disorder.
	Minor (or dysthymic) depression	STRUCTURAL DIAGNOSIS. It is a non-habitual, stable, pervasive but persistent pattern (mood disorder), characterized by depressed mood, low self-esteem and marked decrease in interests and pleasures, for at least 1 year and less than 2 years. It is the evolution of reactive depressive disorder. No manic/hypomanic and/or psychotic symptoms are present. If unmanaged and reworked, it leads to chronicity; therefore, support in psychotherapy, and brief drug therapy to promote psychic change is mandatory. If it persists for more than 2 years it becomes a major depressive disorder. FUNCTIONAL DIAGNOSIS. There must be at least 5 of the following 9 clinical criteria of major depressive disorder.
	Major (or chronic) depression	STRUCTURAL DIAGNOSIS. It is a habitual, stable, persistent, and pervasive pattern (personality disorder), characterized by depressed mood, low self-esteem, and marked decrease in interests and pleasures, for more than 2 years, continuously and uninterruptedly (most of the time, almost every day), and in the absence of manic/hypomanic or psychotic symptoms or clinical conditions that are capable of bringing about the depressive symptoms. Needs clinically approached psychotherapy and the use of psychotropic drugs, in a sustained mode. FUNCTIONAL DIAGNOSIS. At least 5 of the following 9 clinical sub-criteria (of the depressive episode) must be met: Depressed mood, which consists of the external character manifestations in a sad, melancholic, passive, and negative mode, compared to the circumstances and the social-environmental context that instead turns out to be positive or otherwise neutron, thus risking the impairment of the functioning of 1/+ spheres of life (e.g., personal, social, work, affective). Low self-esteem, consisting of having a tendentially negative attitude to life, believing little in oneself or one’s resources, or otherwise in one’s abilities and means, due to insecurity, with a tendency to isolation, loneliness, sedentariness, poor self-care or self-abandonment with/without diminishing social and emotional relationships (affective symptoms). Marked decrease in pleasure in performing interests and activities (anhedonia) that are new or otherwise previously enjoyed or interested, whereas now they arouse fatigue, apathy, fear of failure, boredom, and disinterest. Significant increase or decrease in body weight since the onset of the first depressive symptoms, which may result in eating disorders. Psychomotor agitation or slowing down, in the absence of manic/hypomanic symptoms and/or marked neurotic symptoms (e.g., phobic, obsessive, somatic) with/without alterations in sleep–wake rhythm and one’s natural biorhythm. Perception of lack of energy or easy fatigability (asthenia). Feelings of self-evaluation, restlessness, helplessness, worthlessness, inappropriateness, emptiness, guilt or shame, affecting self-perception and ability to plan. Reduced ability to concentrate and/or memory. Recurrent negative, melancholic or death-related thoughts that are not provoked by actual events (e.g., mourning).
“Mixed depressive manifestations”	Mixed “atypical” form	These are conditions of clinical interest, where the patient manifests depressive symptoms, without fully meeting all criteria or only the structural criteria, but at a more severe level than the subclinical form. They have an extensive negative impact on the patient’s life, such that his or her functioning is mostly impaired, and he or she perceives psychophysical distress and discomfort.
“Mixed depressive manifestations”	Mixed “typical” form	They are conditions of clinical interest, with a different specificity from the pure forms of depressive conditions and depressive disorder. They have an extensive negative impact on the patient’s life, such that their functioning is mostly impaired, and they cause them to feel psychophysical distress and discomfort. They are: “Anxiety-depressive disorder”: these are the depressive disorders with accentuated neurotic psychopathological component (anxious dyslevel, phobias-avoidances, obsessions, anxious generalizations and somatizations), which is not only a symptom but a real psychopathological co-structure side by side with the depressive one, never having more than 4 dysfunctional traits per type of neurotic nature (according to PICI-3 model). “Manic-depressive disorder”: these are the depressive disorders with accentuated manic/hypomanic component, which is not only a symptom but a real psychopathological co-structure side by side with the depressive one, never having more than 4 dysfunctional traits per type of neurotic nature (according to the PICI-3 model). It is synonymous with bipolar disorder. “Psychotic-depressive disorder”: these are the depressive disorders with accentuated psychopathological psychotic component (paranoia, delusions, hallucinations, dissociation), which is not only a symptom but a real psychopathological co-structure side by side with the depressive one, never having more than 4 dysfunctional traits per type of neurotic nature (according to PICI-3 model). “Dramatic-depressive disorder”: these are the depressive disorders with accentuated dramatic psychopathological component (borderline, histrionic, narcissistic, antisocial, psychopathic), which is not only a symptom but a real psychopathological co-structure side by side with the depressive one, never having more than 4 dysfunctional traits per type of neurotic nature (according to PICI-3 model). Short depressive episode of more than 30 days but less than 3 months. Depressive disorder because of drug, alcohol or pharmaceutical use. Depressive disorder because of specific medical condition (e.g., head trauma, brain hemorrhage, cerebral vascular deficits, neurodegenerative dementia, hypothyroidism, hypotestosteronism, and vitamin deficiencies).

Table 4. Perrotta Depressive Symptom Assessment Scale (PDSYA-s). “Level” represents the increasing scale of representation of psychopathological severity about depressive symptoms. The “color” is the exact corresponding of the levels, in its graphical representation. The “specificity” is the mathematical result of the summation between 2 physical quantities: intensity (I understood as subjective perception of pervasiveness of depressive symptoms) and frequency (f, understood as the number of daily repetitions of depressive symptoms), according to individual subjective values ranging from 1 (low) to 3 (high). The “description” is the column of the descriptive details.

Perrotta Depressive Symptom Assessment Scale (PDSYA-s)
Level	Color	Specificity	Description
1	White	1i + 1f	The patient describes his depressive state as low in intensity (1/3) and infrequent (1/3), with symptoms easily manageable and present only when stressful or destabilizing events occur. The patient reports depressive symptoms that are distressing emotional manifestations, which he fails to interpret and generalizes as “depressive symptoms”. Some examples are the following: sadness, frustration, melancholy, emptiness, and bitterness. This level has no clinical relevance and pertains mainly to personal character tendencies, worthy of psychological counseling.
2	Pink	1i + 2f	The patient describes his depressive state as low in intensity (1/3) and medium in frequency (2/3), with manageable symptoms present when stressful or destabilizing events occur. An example is repetitive thoughts of insecurity and/or failure. This level has little clinical relevance and pertains more to personal character tendencies, worthy of occasional psychological counseling and assistance.
3	Green	1i + 3f	The patient describes his depressive state as low in intensity (1/3) but highly frequent (3/3), with symptoms nevertheless manageable and present when stressful or destabilizing events occur, and after them. An example is repetitive thinking of failure (generalized). This level has little clinical relevance and pertains more to personal character tendencies, deserving of psychological assistance (understood as psychological intervention on demand, without specific calendaring).
4	Yellow	2i + 1f	The patient describes his depressive state as moderately intense (2/3) but infrequent (1/3) or otherwise limited to circumscribed circumstances or time, with symptoms not always manageable and present during and after stressful or destabilizing events. This level has medium clinical relevance and pertains to degenerative phenomena resulting from adaptation deficits and brief or short-lived depressive episodes. This level is deserving of psychological support (understood as psychological intervention on demand, but with specific scheduling, punctual cadence, and therapeutic contract by goals).
5	Orange	2i + 2f	The patient describes his or her depressive state as moderately intense (2/3) and moderately frequent (2/3), rarely confined to circumscribed circumstances or time, with symptoms that are unmanageable and present during and after stressful or destabilizing events. This level has medium clinical relevance and pertains to degenerative phenomena resulting from depressive conditions. This level is deserving of psychological support (understood as psychological intervention on demand, but with specific scheduling, punctual cadence, and therapeutic contract by goals).
6	Red	2i + 3f	The patient describes his or her depressive state as moderately intense (2/3) but highly frequent (3/3), rarely confined to circumscribed circumstances or time, with symptoms rarely manageable, and still present during and after stressful or destabilizing events. This level has high clinical relevance and pertains to degenerative phenomena arising from depressive conditions and mixed forms. This level is deserving of psychological support (understood as psychological intervention on demand, but with specific scheduling, punctual cadence and therapeutic contract by goals).
7	Brown	3i + 1f	The patient describes his depressive state as highly intense (3/3) but infrequent (1/3), limited to circumscribed circumstances or time, with symptoms, however, almost never manageable and still present during and after stressful or destabilizing events. This level has high clinical relevance and pertains to degenerative phenomena arising from dysthymia and mixed forms. This level is deserving of psychological therapy (understood as psychological intervention on request or proposal, but with specific calendaring, punctual cadence and therapeutic contract by objectives, with a strong clinical approach).
8	Purple	3i + 2f	The patient describes his or her depressive state as highly intense (3/3) and averagely frequent (2/3), no longer limited to circumscribed circumstances or time periods, and symptoms that are almost never manageable and are present in any case during and after stressful or destabilizing events. This level has high clinical relevance and pertains to degenerative phenomena arising from mixed forms and depressive disorders (reactive and dysthymia). This level is deserving of psychological therapy (understood as psychological intervention on request or proposal, but with specific calendaring, punctual cadence and therapeutic contract by objectives, with a strong clinical approach), with evaluation of the psychopharmacological profile.
9	Black	3i + 3f	The patient describes his depressive state as highly intense (3/3) and highly frequent (3/3), no longer confined to circumscribed circumstances or time and symptoms that are never manageable and still present during and after stressful or destabilizing events. This level has high clinical relevance and pertains to degenerative phenomena arising from mixed forms and dysthymia. This level is deserving of psychological therapy (understood as psychological intervention upon request or proposal, but with specific calendaring, punctual cadence, and therapeutic contract by objectives, with a strong clinical approach), and psychopharmacological support.

Table 5. Perrotta Depressive Symptom Assessment Scale for Therapies (PDSYA-s-t). “Level” represents the increasing scale of representation of psychopathological severity about depressive symptoms. The “color” is the exact corresponding of the levels, in its graphical representation. The “description” is the column for the descriptive listing of the specific level.

Perrotta Depressive Symptom Assessment Scale for Therapies (PDSA-s-t)
Level	Color	Description
1	Green	The patient does not require targeted psychological intervention. Thematic counseling or psychoeducation is suggested.
2	Yellow	The patient needs caregiver-type psychological intervention (occasional and for short cycles).
3	Orange	Patient needs supportive psychological intervention (scheduled and for short cycles), with short psychopharmacological evaluation.
4	Red	Patient requires supportive psychological intervention (scheduled and for medium-to-long cycles), with mid-term psychopharmacological evaluation.
5	Purple	Patient requires therapeutic psychological intervention (scheduled and for medium to long cycles), with medium to long term psychopharmacological evaluation.
6	Black	Patients require therapeutic psychological intervention (scheduled and for medium to long cycles), with also long-term psychopharmacological support.

Table 6. Data collection of PDSYA-Q1, according to the scheme of Kishore et al. [38]. The content of the items is indicated in the following Appendix A.

Item	N	CVR	Interpretation	I-CVI	Interpretation	S-CVI
1	36	0.977	Essential	0.966	Relevant	0.983
2	36	0.901	Essential	0.945	Relevant
3	36	0.877	Essential	0.972	Relevant
4	36	0.967	Essential	0.933	Relevant
5	36	0.931	Essential	0.935	Relevant
6	36	0.819	Essential	0.936	Relevant
7	36	0.879	Essential	0.972	Relevant
8	36	0.811	Essential	0.938	Relevant
9	36	0.855	Essential	0.941	Relevant
10	36	0.902	Essential	1.000	Relevant
11	36	0.933	Essential	1.000	Relevant
12	36	0.865	Essential	1.000	Relevant
13	36	0.897	Essential	1.000	Relevant
14	36	0.923	Essential	1.000	Relevant
15	36	0.821	Essential	1.000	Relevant
16	36	0.878	Essential	1.000	Relevant
17	36	0.817	Essential	1.000	Relevant
18	36	0.924	Essential	1.000	Relevant
19	36	0.955	Essential	1.000	Relevant
20	36	0.926	Essential	1.000	Relevant
21	36	0.879	Essential	1.000	Relevant
22	36	0.904	Essential	1.000	Relevant
23	36	0.982	Essential	1.000	Relevant
24	36	0.819	Essential	1.000	Relevant
25	36	0.869	Essential	1.000	Relevant
26	36	0.841	Essential	1.000	Relevant
27	36	0.966	Essential	1.000	Relevant

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Differential Diagnosis in Disorders with Depressive Symptoms: Exact Clinical Framing and Proposal of the “Perrotta Depressive Symptoms Assessment”

Abstract