The question of Mixed States (MS) has been much debated over the centuries, from Hippocrates and Aristotle till the present days; the construct has been revised in the Diagnostic and Statistical Manual for Mental Disorders (fifth edition) (DSM-5) [1]. In the first decades of the XX century, Kraepelin described six different types of MS based on the combination of non-unison stable variations in the three domains of mood, thought, and psychomotricity [2-4]. These types included depressive or anxious mania, excited depression, mania with thought poverty, mania with stupor, depression with flight of ideas, and inhibited mania. The operational definition of “mixedness” in the DSM classification underwent a substantial change, moving MS from a core episode to a clinical specifier for both depressive and bipolar disorders (from DSM-III [5] to DSM-5). The DSM-5 definition of mixed depression (MxD) consists in the addition of the “with mixed features” specifier (DSM-5 MFS) to a diagnosis of a major depressive episode (MDE) in either unipolar or bipolar patients with at least three of the following (hypo)manic symptoms: elevated or expansive mood; inflated self-esteem or grandiosity; being more talkative than usual or feeling pressure to keep talking; flight of ideas or racing thoughts; distractibility; increase in energy or goal-directed activity; increased or excessive involvement in activities that have a high potential for painful consequences, and decreased need for sleep. The new DSM-5 classification mirrors the conceptualization of mood disorders along a spectrum ranging from pure unipolar depression to pure mania, through different presentation patterns of depressive and manic symptoms [6-8].

However, various issues should be mentioned. For instance, the relevance of this nosographic entity is underestimated and several clinical manifestations of patients with mood disorders might not be recognized, leading to an under-diagnosis of mixed episodes and their phenomenological presentations [9-11]. Considering the lower response to standardized treatments of these forms compared to pure presentations of depressive syndromes [7, 12-14], the correct diagnosis and treatment of these patients is central to psychiatric care.

Therefore, potential alternatives to DSM criteria for MxD have been proposed in the literature with a significant contribution by some Italian authors. For example, Benazzi considered a minimum of three numbers of hypomanic symptoms (without specifying which ones) that are present within the depressive state and with a score on the Hypomania Interview Guide > 7 [15-17]. Koukopoulos’ construct of MxD focuses on the dysphoric and excitative components, and its diagnosis requires the presence of at least three of the following symptoms during an MDE: psychic agitation or inner tension; racing or crowded thoughts; irritability or unprovoked feelings of rage; absence of retardation; talkativeness; dramatic description of suffering or frequent spells of weeping; mood lability and marked emotional reactivity and early insomnia [18-20].

More recently, the Activity, Cognition, and Emotion (ACE) model has become a valid proposed approach that considers mood disorders as a combination of symptoms across these three domains, varying over time [21, 22]. Each symptom may be defined in terms of severity dimension. For depression, activity symptoms include loss of energy, alteration of sleep and appetite, reduced engagement in normal activities, and psychomotor agitation or retardation; cognitive symptoms include diminished concentration and indecisiveness, while emotional symptoms are sadness, hopelessness, worthlessness, and guilt. For mania, activity symptoms include a decreased need for sleep, an increase in goal-directed activity, psychomotor agitation, and heightened talkativeness; cognitive symptoms include racing thoughts and distractibility, while emotion symptoms are represented by euphoria and inflated self-esteem. Therefore, clinicians could conceptualize various nuanced aspects of clinical presentations that may give us novel insights, facilitating research and enhancing the recognition and understanding of mood disorders [23-27].

Current pharmacological guidelines, largely based on evidence derived from clinical trials on bipolar patients who met the DSM–IV definition of either manic or depressive episodes [28], provide insufficient decision support to clinicians for adequate treatment in patients affected by MDE with mixed features [12, 29-32]. Given the epidemiological and psychopathological relevance of this topic in the field of mood disorders, the evident gap related to DSM-5 criteria, and the recent literature updates in the treatment of mood disorders, we conducted a survey on the attitudes of Italian psychiatrists towards the clinical entity of MxD. Specifically, this study aimed to investigate the relevance of this framework in daily clinical practice, focusing on the diagnostic and therapeutic approaches adopted as well as on the psychopathological role model of a clinical entity still being debated.

The survey was completed by 395 psychiatrists. We excluded residents attending the first and second years of specialization. This reduced the number of available questionnaires to 369. Twenty-seven questionnaires were excluded because they had not been filled in properly. The sociodemographic characteristics of the participants are reported in Table 1. Among the 342 responders, 57.31% were females, and the median age was 38 (IQR: 34-50). Most of the participants had completed their training (89.47%). The median number of working years for all the participants was 6 (IQR: 2-19). Almost half of the responders had attended and completed a psychotherapy school (42.11%), 44 had obtained a Ph.D. degree, and 78 had a master's degree. Two hundred and fifty-six participants worked in services afferent to a public Department of Mental Health (193 in Adult Mental Health Centres, 63 in Psychiatric Diagnosis and Treatment Hospital Units), 65 were employed at University Hospitals, and 21 in other settings. Responders from northeast Italy were 64, 83 from the northwest, 59 from the center, 59 from the south of Italy, and the remaining 77 from the Islands.

A detailed description of the answers to the questionnaire items is reported in Table 2, in which only the participants that answered “Yes” to the question “Do you know what MxD is?” are included (N=320). More than half of the responders (56.25%) reported having performed a clinical diagnosis of MxD without using any psychometric scales or questionnaires. Conversely, the most commonly used assessment tools were the YMRS (N = 69) and the HCL-32 (N = 41). The KMxD-RS was used by only 21.43% (30 participants over 140) of those reporting the use of diagnostic tools.

The most common prescription strategies are reported in Table 3. Regarding polytherapy, the most commonly prescribed antipsychotics were, in descending order, olanzapine, quetiapine, aripiprazole, risperidone, and lurasidone, irrespective of the polypharmacy prescription approach. The most used mood stabilizers, in descending order, were valproate, lithium, lamotrigine, (ox)carbazepine, pregabalin/gabapentin, and topiramate, regardless of the polypharmacy prescription pattern. Finally, psychiatrists who opted for prescribing antidepressants by choosing a polypharmacy strategy preferred selective serotonin reuptake inhibitors (SSRI) over serotonin-norepinephrine reuptake inhibitors (SNRI); vortioxetine, trazodone, and bupropion.

We asked the participants if they took into account DSM-5 MxD criteria in the diagnostic approach and 227 (70.94%) answered in affirmative. The estimated frequency of MxD diagnosis among depressed patients was significantly lower for psychiatrists who answered that they referred to DSM-5 (17.50% vs. 30.00%, p < 0.001).

We also inquired about the standpoint regarding the conceptualization of depressive disorders: 199 of the participants answered that they supported the “unitary model”, 101 the “binary model” and 20 did not know. We excluded the latter and compared the other variables among the remaining 300 subjects. The respondents who agreed with the “unitary model” were younger than the others (37 vs 42 years old, p = 0.039). Among the respondents who opted for the “binary model”, we found a higher percentage of participants who affirmed that they considered DSM-5 criteria for the recognition of MxD compared to those who opted for the “unitary model” (81.19% vs. 64.82%, p = 0.003). Conversely, those who chose the “unitary model” used the Koukopoulos criteria for the diagnosis more frequently than the other group (13.07% vs. 3.95%, p = 0.013). The rate of respondents who indicated that they do not prescribe antidepressants for treating MxD was greater in the “unitary model subgroup” than in the “binary model” subgroup (35.68% vs 20.79%, p = 0.008). (Table 4).

This is the first study to explore the knowledge and prescriptive attitudes towards MxD of psychiatrists working in different clinical settings across Italy. We aimed to investigate psychiatrists’ awareness of the concept of MxD, also examining the assessment of first-time diagnosed patients and the prescription patterns adopted.

Almost all the participants (93.6%) answered that they were acquainted with the clinical entity of MxD. Only 23.43% of the respondents considered the level of training provided on this topic to be adequate, whereas twice that percentage (46.07%) rated it to be from “barely enough” to “seriously inadequate”. Similarly, only 5% of the sample ranked the attention and time dedicated to MxD in post-residency scientific meetings as “fully adequate”

The reported prevalence of MxD diagnosis varies from 0% to 95% of total MDEs with a median value of 20% (IQR: 10-30%). This wide range of variability is not surprising since it is in line with the existing literature [7, 18, 44, 45] and might be mostly due to the absence of criteria univocally defining MxD [46-49].

Overall, the nosologic reorganization of MS implemented by DSM-5 reaches only a partial consensus among the participants in our survey. Only 7,5% of the surveyed psychiatrists considered the DSM-5 criteria for MxD to be fully adequate in the description of this clinical entity. On the other hand, a large majority of them evaluated the new systematization to be better than that of DSM-IV-Text Revision. We could hypothesize that one of the main reasons supporting only the partial agreement with DSM- 5 MFS criteria was the validity of the selected mixed symptoms. In fact, participants identified irritability, emotional liability, and psychomotor agitation/psychic tension as the symptoms “suggestive” of the diagnosis of MxD and more frequently recorded, based on their own clinical experience. None of these symptoms are included among the DSM-5 criteria for MxD because of the choice made by the DSM-5 - task force to exclude overlapping manifestations between episodes of opposite polarity.

Nevertheless, those symptoms indicated by participants to be rarely found during MDE with mixed features, namely “inflated self-esteem”, “hypersexuality”, “elevated mood” and “involvement in risky or dangerous activities”, belong to the category of non-overlapping (hypo)manic symptoms. Consistent with previous studies, our survey highlights the criticisms toward the DSM-5 construct of MxD. Indeed, as argued by other authors, the decision to discard the “overlapping symptoms” and include pure manic manifestations, such as “elevated mood” or “inflated self-esteem”, led to the development of an operational model of MxD that is not consistent with the phenomenological reality, disregarding the dysphoric and excitatory components in these patients [8, 50-54].

Regarding the assessment of contrapolar symptoms, the use of specific scales or questionnaires was practiced only by around 45% of participants. This may be related to the scarce attitude of the psychiatrists to the use of psychometric instruments in routine clinical practice, likely due to lack of time and adequate training [42, 55, 56]. Among the assessment tools listed, the YMRS was the one most used, followed by the HCL-32 and the SCID-5- CV). Few participants chose the KMxD-RS, a questionnaire specifically developed for assessing the diagnostic criteria of this alternative construct of MxD. The KMxD-RS appears to be less known, with increased use among participants working in Central Italy, probably due to the influence of the work of Athanasios Koukopoulos' Roman group in the training of psychiatrists working in that area.

In this survey, we also investigated the prescriptive attitudes adopted for the treatment of depressive episodes with mixed features. Firstly, we asked which approach was most frequently used between mono- and polytherapy, obtaining heterogeneous responses. The pharmacological management of MS is an insidious challenge for psychiatrists. Historically, pharmacotherapy of MS has represented an unmet need in the international guidelines for the treatment of mood disorders, and currently, no drugs have been approved for the treatment of MxD, although pharmacological recommendations are available [57-61].

Almost one-third of respondents selected antidepressants in combination with mood stabilizers or antipsychotics. SSRIs represented the antidepressant class most widely prescribed. Among the mood stabilizers, valproate and lithium were the first choices in association with antidepressants, whereas olanzapine and quetiapine were the preferred choice of antipsychotics. Antidepressant monotherapy was selected by around 10% of the psychiatrists. Overall, the prescriptive attitude towards antidepressants in MxD appears to be in line with the guidelines and pharmacological recommendations. Indeed, antidepressant monotherapy is discouraged, and reservations are expressed about their prescription in the maintenance treatment, if associated with mood stabilizers or antipsychotics [12, 62-64].

We also found that the use of antidepressants was less reported by those participants who preferred the unitary model. This might be attributed to the opposition to the use of antidepressants expressed by previous authors who support a spectrum approach to mood disorders [65-71].

The association of mood stabilizers with second-generation antipsychotics (SGAs) was found to be the prevailing prescriptive pattern. Valproate and lithium among mood stabilizers, and quetiapine and olanzapine among antipsychotics, were indicated as the drugs most used in such a combination. Similarly, valproate, quetiapine, lithium, and olanzapine resulted in the most used drugs also in monotherapy. These findings suggest an alignment of prescribing practice with the available literature evidence. Indeed, most of the aforementioned recommendations for the treatment of MxD indicate olanzapine and quetiapine as first-line or second-line options, either in monotherapy or in association with a mood stabilizer. On the other hand, lurasidone and asenapine were chosen by few participants, although they are included among the most widely recommended antipsychotics along with olanzapine and quetiapine. This data fits into a less prescriptive attitude towards these SGAs by Italian psychiatrists, as documented by the Italian Medicines Agency (AIFA) report on drug’ consumption. Regarding lurasidone, this trend might be explained by the fact that it was just recently introduced to the Italian market [72], while the progressive decreasing prescription of asenapine might be due to a profile of particularly unpleasant side effects [73, 74].

As regards the mood stabilizers, valproate and lithium were the most considered drugs, irrespective of the chosen therapeutic regimen. Both these drugs are mentioned among potential first-line or second-line options either in monotherapy or in association with an SGA (olanzapine, quetiapine, or lurasidone). However, mood stabilizers monotherapy is mostly recommended for maintenance treatment since the available evidence on their efficacy in the acute treatment is weak, especially compared to SGAs [63]. The percentage of our respondents reporting the use of lithium is quite remarkable. This result is almost coinciding with the rate of participants who answered that they considered lithium for the treatment of depressive episodes with mixed features in a recent survey involving young Italian psychiatrists [75]. Therefore, our results confirm an incremental trend in lithium’s prescription after decades of relative marginalization of this pharmacological agent in psychiatric practice [76, 77].

Finally, we asked participants to indicate which theoretical model they found the most reliable for the classification of depression. We suggested two possible models: the Kraepelinian unitary spectrum view of mood disorders and Leonhard's binary model, which considers bipolar and unipolar depression as two separate psychopathological entities [78, 79]. Over 60% of our sample expressed their preference for the spectrum view, while 30% supported the Leonhardian dichotomic model, and around 6% did not express any preference. The respondents in favor of the unitary model were significantly younger than those who opted for the binary model. It can be hypothesized that younger psychiatrists rely on a dimensional and spectrum approach to the diagnosis of affective and psychiatric disorders in general. On the other hand, those who preferred the dual view might be still anchored on the categorical approach introduced by DSM III, which divided for the first time, Kraepelin's broad concept of manic-depressive insanity (MDI) into the two distinct diagnoses of bipolar disorder and major depressive disorder, therefore introducing a distinction between unipolar and bipolar depression [80].

This study has several strengths and limitations. As previously underlined, this is the first survey aimed at exploring the psychopathological, diagnostic, and therapeutic approaches toward the clinical entity of MxD among a large sample of Italian psychiatrists, with a quite homogeneous geographical representation, working in different clinical settings. One of the limitations is that we collected few responses from academic psychiatrists who may offer a perspective that is more aligned with the latest literature evidence on psychopathology and treatment strategies of MS. Moreover, the choice to rely on an online survey could have implied a sort of recruiting bias with the self-selection of a younger and more technologically inclined sample. Finally, although the survey was conducted anonymously, we cannot exclude that several answers, especially those concerning the pharmacological approach, could be affected by a potential desirability bias rather than reflect the real attitudes in the daily clinical practice.

The explorative nature of this survey highlights the clinical relevance of mixed depression within the field of affective disorders. The resulting heterogeneity of diagnostic and therapeutic approaches of MxD reflects the need for further studies on this topic. They would be aimed at clarifying the psychopathological structure of MxD in order to develop future univocal diagnostic criteria for the correct identification of patients and for conducting specifically targeted clinical trials. Another aspect arising from this study is the lack of attention given to MxD and MS during residency training and postgraduate training events. Therefore, there appears to be an urgent need for more specific activities and training programs to fill this gap.