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In reviewing the scientific studies upon which the DSM-5 work group based its conclusions, augmented by an extensive review of this literature, we conclude that there is weak evidence – historical or scientific – that supports the DSM-5 definition of mixed features for depression. The DSM-5 task force has taken the view that its definition is based on excluding ‘overlapping’ mood criteria, those which occur both in depression and mania. Those overlapping criteria – like psychomotor agitation and irritability and mood lability – are, unfortunately, the core features of mixed depression. Certainly, criteria may be common for an illness but nonspecific, but it makes no scientific sense to exclude them entirely, without any scientific evidence that the remaining criteria are sufficiently sensitive to identify that condition.
This lack of an evidence-based approach highlights how the primary DSM-5 motivation in deciding how to define these mixed features criteria seems to be more ‘pragmatic’ than anything else: the theoretical wish to avoid overdiagnosis, even if the diagnosis one then makes is invalid.
Nor is it enough, we think, to conceive of mixed states as simply combinations of depressive and DSM-defined manic/hypomanic symptoms. The concept of agitation and psychomotor excitement is the key point, not DSM-defined manic symptoms.
Today many authors take for granted that mixed syndromes derive from a combination of depressive and manic/hypomanic symptoms. Kraepelin himself , however, warns to be careful about such view:
in the place of volitional inhibition, anxious excitement appears not very infrequently. The patients display a more or less lively restlessness… Specht , Thalbitzer , and also Dreyfus  are inclined to interpret that kind of anxious excitement from the point of view of mixed states. It is said to be a case here of a conjunction of depression with the manic morbid symptoms of volitional excitement. Taking the contrary view, Westphal and Koelpin  have pointed out that ‘the excitement represents an immediate outflow of anxiety, and therefore cannot be regarded as a manic component of the morbid state’…. It however appears to me hazardous to approach circumstances, which are certainly very involved, with such simple conceptions.
Griesinger  also gives us an important insight that should be central to this discussion:
By using the expression ‘psychic depressive states’ we did not mean to imply that the basic nature of these states is inactivity and weakness and suppression [depression] of the psychic or cerebral processes that underlie them. We have much more reason to assume that very intense states of irritation of the brain and excitation of the psychic processes are very often the cause of such states; but the end result of these [psychic and cerebral] states as far as mood is concerned is a state of depression or psychic pain.
Certainly, the rising of depressive, painful mood states from excitatory processes constitutes a psychopathological enigma from ancient times until today and is a serious diagnostic and therapeutic problem. Yet, psychomotor agitation and deep psychic suffering are very common in neuropsychiatric illnesses, even outside mood disorders (e.g., Alzheimer disease). Even in those other illnesses, it is not clear whether psychic suffering causes agitation or the reverse.
We think that, at present, these symptoms should not be called ‘manic/hypomanic’ symptoms but excitatory symptoms, following Griesinger's use of the phrase ‘excitation of the psychic processes’ .
Indeed, the excitatory symptoms of mixed depression are qualitatively different from typical manic/hypomanic symptoms. Patients with mixed depression have none of the characteristics of manic/hypomanic behaviour: they lack expansiveness, easy and light contact with others, and easy performance of activities. Depressive excitatory symptoms lead to just the opposite. Patients are shut in their pain, unable to perform anything, full of lamentation. Their restlessness is aimless; they suffer enormously. The coexistence of depressive and manic/hypomanic symptoms is often found in the transitional periods between two phases of opposite polarity, but in these cases, the clinical picture is different from that of a stable mixed depressive episode. The mixed hypomanic patient does not suffer of the typical anguish or inner agitation of the mixed depressive episode.
In line with this perspective, it is not conceivable to establish the diagnosis of depression with mixed features on a very rare clinical picture (depression plus clear hypomanic symptoms) as proposed by DSM-5, to the detriment of the real and very common clinical picture of mixed depression, characterized by depressive and excitatory symptoms and representing the most dramatic expression of psychic suffering. The risk of suicide, often associated with mixed depression [60-62], grows from this suffering. A patient, who attempted suicide, said:
I did not want to put an end to my life. I do love life. I just wanted to put an end to this awful (psychic) agitation’. Griesinger's ‘very intense states of irritation of the brain and excitation of the psychic processes
must be of a different nature than the processes that underlie manic/hypomanic symptoms.
The above historical and phenomenological considerations can be augmented with an analysis of the DSM-5 approach to mixed depression using current scientific studies, as reviewed in this study.
According to the findings reported, along with the classic literature, modern scientific papers show that the great majority of patients with mixed depression display symptoms such as agitation, irritability, racing/crowded thoughts, and insomnia, and mostly do not present DSM-5 proposed symptoms.
However, as mentioned earlier, a few researchers report hypomanic expansive symptoms in mixed depression, which merits several considerations. First, in those studies, the frequency of expansive symptoms is very low (usually around 10%) among patients with depressive episodes, while the frequency of the depressive excitatory symptoms in other studies is at least threefold higher. Second, these symptoms are usually detected with specific DSM-based diagnostic tools, which mean that patients are not uniformly screened for other manic/hypomanic or excitatory symptoms that may not be captured by DSM criteria. In other words, one finds what one's DSM-related tools make it possible to find and to then one confirms the DSM-based diagnosis. This tautological approach does not have the possibility of any external validation (or disconfirmation). Third, we can accept the notion of mixed hypomania as a separate condition, different from and less frequent than mixed depression. The mistake DSM-5 makes is to use the concept of and evidence for mixed hypomania to define mixed depression.
In our opinion, the DSM-5 criteria, as they stand now, will leave many patients with mixed depression undiagnosed. Our hypothesis is shared with other research groups. Pae et al. , for example, stated: ‘The DSM-5 proposal also excludes agitation. These criteria, although sensitive, may have low specificity, which may have been the concern of DSM-5 task force members who are concerned about false positives. However, if the mixed state is defined too narrowly, we will also have many false negatives.’
The decision to base the DSM-5 diagnosis solely on excluding overlapping symptoms was erroneous, as demonstrated by this review of the literature, which shows that such symptoms as psychic or motor agitation and irritability are the core symptoms of a mixed depression. Maj  recently stated:
The definition of major depression with mixed features is likely to be controversial, as it includes typical manic symptoms (such as elevated mood and grandiosity) that have been found to be rare among patients with mixed depression, while excluding symptoms (such as irritability, psychomotor agitation and distractibility) that are frequently reported in mixed depression.
In conclusion, the scientific and historical evidence does not appear to support the DSM-5 criteria for depression with mixed features. Instead, because of DSM-5 criteria, many patients with mixed depression likely will be inadequately diagnosed and treated. Instead, there is much more evidence that supports the clinical validity of an alternative definition of agitated depression and mixed depression, as described above.
Of course, our hypotheses could be confirmed or not by future studies; the same is true for DSM-5 nosologic construct. Looking back over sixty years and five editions of DSM, it is clear that our nosological systems are not rigid, where diagnoses, once established, remain stable over decades. On the contrary, our taxonomy is evolving, according to new clinical and neurobiological findings. It should not be otherwise.