• affective disorders;
  • antidepressives;
  • bipolar disorder;
  • depression


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References


To review the DSM-5 proposed criteria for mixed depression in light of robust and consistent historical and scientific evidence.


An extensive historical search, a systematic review of the papers used by DSM-5 as reference papers, and a PubMed search were performed.


As Hippocrates, depressive mixed states have been described as conditions of intense psychic suffering, consisting of depressed mood, inner tension, restlessness, and aimless psychomotor agitation. In DSM-5, new criteria are proposed for a mixed features specifier, as part of depression either in major depressive disorder (MDD) or bipolar disorder. Those criteria require, as diagnostically specific, manic/hypomanic symptoms that are the least common kinds of symptoms that actually arise in depressive mixed states. The DSM-5 proposal is based, almost entirely, on a speculative wish to avoid ‘overlapping’ manic and depressive symptoms. Mixed states are, in fact, nothing but overlapping manic and depressive symptoms.


In this article, we review the psychopathology and research on mixed depressive states, and try to demonstrate that the DSM-5 proposal has weak scientific basis and does not identify a large number of mixed depressive states. This may be harmful because of the different treatment required by these conditions.

Clinical recommendations
  • Historical and scientific evidence shows that patients with mixed depression present excitatory symptoms such as psychomotor agitation, irritability, racing and crowded thoughts, and logorrhea. This clinical picture is characterized, at the same time, by depressed mood, anxiety, profound despair, anguish, and high risk of suicide.
  • DSM-5 proposed criteria for mixed depression suggest, along with a major depressive episode, the presence of at least three of seven frankly hypomanic symptoms. This clinical picture is extremely rare in mixed depressive states and does not target the great suffering linked to mixed depression.
  • The application of the DSM-5 proposed criteria for mixed depression will lead to under- or misdiagnosis of these patients. An inadequate treatment (i.e., antidepressant treatment) could worsen the agitation and increase the risk of suicide.
Additional comments
  • The clinical data presented in this study are based on naturalistic longitudinal clinical studies.
  • Contrary to our view, in the current literature, one finds several papers reporting pure hypomanic symptoms during depressive episodes. This clinical picture seems to be rare and more similar to a mixed hypomanic than a mixed depressive state.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

The loss of agitation

From its inception, the American psychiatric world, as expressed in the DSM system, has been uneasy with mixed forms of affective disorders. In the first edition of 1952 [1], DSM placed mixed features in a peripheral position, together with continuous circular forms, as part of ‘manic depressive reaction, other.’ In the second edition of 1968 [2], under the title ‘Other major affective disorder’, DSM stated: ‘Major affective disorders for which a more specific diagnosis has not been made are included here’, such as ‘mixed manic-depressive illness, in which manic and depressive symptoms appear almost simultaneously’. A key shift in DSM-III [3], published in 1980, was the introduction of the term ‘bipolar disorder’ in place of manic-depressive illness. In this new context, bipolar disorder, mixed is defined as follows: ‘current (or most recent) episode involves the full symptomatic picture of both manic and major depressive episodes, intermixed or rapidly alternating every few days’. This definition is kept substantially identical, with the exception of the duration criterion of two weeks for depressive symptoms, in DSM-III-R, published in 1987 [4]. DSM-IV, 1994 [5], and DSM-IV-TR, 2000 [6], narrowed the definition of mixed episodes further, by specifically requiring the simultaneous presence of a full manic and a full depressive episode. This DSM-IV definition has proven, with almost two decades of experience, to be of little clinical utility because this clinical picture is very rare.

DSM-III made another error: it made psychomotor agitation diagnostically irrelevant. Agitation was listed and made equivalent to psychomotor retardation, as part of a fifth criterion for a major depressive episode: ‘psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)’. This relegation of psychomotor agitation as just part of a subcriterion of major depression, made it easy to diagnose the same condition, a major depressive episode, in someone who had severe agitation as well as in someone who had no agitation at all. Psychomotor agitation, long seen as a hallmark of a special kind of mood state (as explained below), became diagnostically nonspecific.

As is acknowledged by researchers and historians, DSM revisions are not uniquely based on scientific evidence. They are meant to serve many functions – administrative, legal, financial, educational – in a word ‘pragmatic’ [7] – and among these functions, it was not always easy to put science always at the first rank, as some past DSM leaders [8] and some historians [9] admit.

Before DSM-III, the only American classification system, that was solely and completely based on scientific evidence, was the Research Diagnostic Criteria [10]. There, agitated depression was considered a subtype of major depressive disorder and supplied with excellent diagnostic criteria. Unfortunately, the RDC criteria for agitated depression were not carried over into DSM-III or -IV.

In recent years, a growing number of psychiatrists [11-20] have expressed disenchantment with the official view, proposing agitated depression as a mixed form of affective disorders. In a previous study of our group [21], we proposed, for the mixed depressive syndromes with psychomotor agitation, the traditional name of ‘Agitated depression’ according to the original RDC [10]: the presence of at least two of the following manifestations of psychomotor agitation (not mere subjective anxiety) for several days during the current episode: pacing; handwringing; unable to sit still; pulling or rubbing on hair, skin, clothing, or other objects; outburst of complaining or shouting; and talking on and on or ‘can't seem to stop talking’. In other words, psychomotor agitation, when present, is enough to make the diagnosis. In this way, classic ‘agitated depression’, the most dramatic form of mixed depressive state, would keep its proper name and would be clearly distinguished from the other forms of mixed depressive states, without psychomotor agitation, for which we have proposed the name ‘mixed depression’, the phenomenology of which we will now describe in some detail.

Psychomotor agitation is present in many cases, but not in all. Depressed, anxious mood and inner, psychic agitation dominate the clinical picture of mixed depression. In the cases without psychomotor agitation, inner unrest is the main symptom. This inner agitation makes the patient very anxious and fearful. And this is very common in patients with mixed depression, as also confirmed by a very recent study [22].

Patients describe this intense inner tension with the use of metaphors such as: ‘I feel like I'm bursting inside’, or ‘I feel a violent force inside me as if I wanted to smash everything’, or ‘I feel there are blades tearing through my guts’. They describe an internal shaking or an electrical current passing through the body. This tension is also manifested as muscular tension or pains. Diastolic blood pressure is sometimes found to be increased to >90–100 mmHg. The inner unrest manifests itself also with irritability or feelings of unprovoked rage. In other cases, there is irritability and, at times, verbal and sometimes physical violence, usually within the family environment as noted by Lange [23]. In extreme cases, this rage combined with hopelessness is the cause of the violent character of suicide attempts (sometimes called raptus melancholicus). Many patients suffering from agitated depression complain of a disturbance of the train of thought that they call crowded or racing thoughts or other similar names. These rapid thoughts are not expressed verbally but patients are tormented by them. In contrast, flight of ideas in manic patients is expressed verbally in an abundance of words or pressured or clearly logorrheic speech. In manic flight of ideas, thoughts come and go rapidly as if they were hunting each other or continuously overlapping without any link between them. Depressive ruminations are different also from both manic flight of ideas and mixed depressive accelerated thinking. Pure depressive ruminations consist only of a few thoughts that carry the anxieties and fears of the patient, and they are constantly present or recur frequently. Patients complain of their content, not of their course. There are naturally cases of transition between crowded thoughts and ruminations and making the distinction may be difficult. Motor agitation and racing or crowded thoughts appear to have an inverse relationship: mental excitement is more frequent and more intense in patients who do not show marked motor agitation. In mixed depression, speech shows little inhibition; it is abundant and, in some cases, resembles the pressured speech of manic patients. Psychic suffering is very intense, often unbearable, and expressed in a dramatic way. Because of the characteristic great energy and impulsivity of mixed depression, the risk of suicide is very high (‘I wanted to kill myself to stop my agitation’ a patient once said). Lability of mood and emotional reactivity is also characteristic of the clinical picture of mixed depression. In contrast to the absence of retardation in speech and movement, there is an inhibition of purposeful activity, which in the more severe cases is nearly complete. In mild forms, the patient is quite active and sometimes anxiously hyperactive. Anhedonia and lack of interest are marked in all cases. Early insomnia, often sustained by racing thoughts, is common [24].

We have proposed specific diagnostic criteria, presently under validation, for these patients with ‘Mixed depression’ (Table 1).

Table 1. Mixed Depression without psychomotor agitation diagnostic criteria, proposed by Koukopoulos et al. [21]
Along with Major Depression, at least three of the following symptoms must be present:
 1. Inner tension/agitation
 2. Racing or crowded thoughts
 3. Irritability or unprovoked feeling of rage
 4. Absence of signs of retardation
 5. Talkativeness
 6. Dramatic description of suffering or frequent spells of weeping
 7. Mood lability and marked emotional reactivity
 8. Early insomnia


Now, the DSM-5 [25] proposes the following criteria for a Major Depressive Episode with Mixed Features, criteria which could be applied either to major depressive disorder (MDD) or bipolar disorder (Table 2).

Table 2. DSM-5 mixed features specifier of depression, proposed criteria
If predominantly Depressed, full criteria are met for a Major Depressive Episode, and at least three of the following symptoms are present nearly every day during the episode
 1. Elevated, expansive mood
 2. Inflated self-esteem or grandiosity
 3. More talkative than usual or pressure to keep talking
 4. Flight of ideas or subjective experience that thoughts are racing
 5. Increase in energy or goal directed activity (either socially, at work or school, or sexually)
 6. Increased or excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
 7. Decreased need for sleep (feeling rested despite sleeping less than usual (to be contrasted from insomnia)
Mixed symptoms are observable by others and represent a change from the person's usual behaviour
For those who meet full episode criteria for both Mania and Depression simultaneously, they should be labeled as having a Manic Episode, with mixed features, due to the marked impairment and clinical severity of full mania
The mixed symptom specifier can apply to depressive episodes experienced in Major Depressive Disorder, Bipolar I disorders, Bipolar II disorders, and Bipolar Disorder Not Elsewhere Classified
The mixed symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment)

In our clinical practice, we have seen the 3rd and 4th criterion (namely, more talkative than usual or pressure to keep talking, and flight of ideas or subjective experience that thoughts are racing) frequently in mixed depression, but the other five criteria are extremely rare, if ever present.

Aims of the study

The aim of this study was to provide an extensive overview over the psychopathological clinical picture of mixed depression, reporting selected findings from classic and modern scientific literature. Furthermore, we aimed to present the hypothesis that the forthcoming DSM-5 criteria for mixed depression have a poor clinical utility and to suggest that an alternative set of symptoms could be adopted to make the diagnosis of mixed depression possible.

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

An extensive historical review of the major works about mixed depression was performed. Furthermore, we systematically reviewed the papers used as reference papers by DSM-5 Mood Disorders Work Group. Finally, a PubMed search was performed to examine articles published from 1994 through September 2012 using the following key words: ‘agitated depression’ OR ‘“mixed depressive state’ OR ‘depressive mixed state’ OR ‘mixed depressive syndrome’. Given the extent of the psychiatric literature on this topic, the papers are not systematically reviewed, but important relevant references are used to supplement the discussion. Original articles that clearly described the clinical picture of patients with mixed depressive episodes were selected; moreover, in case of repetitive studies of the same research groups based on the same, or very similar, sample of patients with mixed depression, only the most recent study was taken into consideration. Review papers, letter to editor, and papers written in other languages than English were excluded.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

The evidence of history: mixed depression in classic literature

Since ancient times, melancholia often was described with excitatory symptoms.

Hippocrates (460–377 A.C) [26] writes in Diseases II

Anxiety: The patient feels something like a thorn stinging his innards. He flees from light and from people, loves the dark and he is caught by panic… he is terrified and sees frightening visions, dreadful nightmares and sometimes, dead people. The disease attacks most people in spring.

He also writes: ‘If fear (phobos) or distress (dysthymia) last for a long time, it is melancholia’. Melancholia was seen as having many variations, among which anxiety and agitation, reflecting psychomotor excitation, were prominently mixed with core depressive symptoms of sad mood and anhedonia.

Aretaeus of Cappadocia (1st century AD) [27] writes that melancholics can become easily angry, and stated that melancholics suffer from ‘violent rage and sadness and awful dejection’.

Such descriptions are found repeatedly in ancient Greek and Roman writers. In the Islamic world, the same observations were made. In the 10th century AD, Ibn Imran, who wrote the first monograph in the world solely devoted to melancholia, observed that melancholia can be defined by ‘fears and doubts that seize one's soul and engender panic and fright’ [28].

Modern Western physicians continued to replicate these ancient truths. Heinroth [29] speaks of ‘melancholia mixta catholica’ (completely mixed melancholia) and of ‘melancholia furens’ (rageful melancholia). Benjamin Rush [30] writes about Hypochondriasis that ‘the patients are for a while peevish and sometimes irascible … they quarrel with their friends and relations’. Griesinger [31] considered melancholia a disease of the affect, distinguishing the affects in two major classes: the expansive, affirmative ones and the depressive, negative ones. He placed rage in the intermediate position. He described ‘melancholia in the strict sense’ and ‘melancholia with destructive tendencies’. He considered anger a mixed affect.

Jean Pierre Falret [32] describes ‘anxious melancholia’ as follows:

the patients who move incessantly and get agitated, who bother all their unfortunate companions, their servants, etc ordinarily do not have the premeditated design nor the actual intention of being turbulent or hostile to anyone; it seems that they only shout, sing, cry and perform rapid movements in order to escape from a painful internal state, from a more or less intense anxiety.

Similarly, Jules Baillarger [33] writes of patients who have symptoms of agitation during their melancholia.

The first to use the term ‘melancholia agitans’ was Franz Richarz in 1858 [34], with the term for agitation chosen to emphasize aimless and purposeless motor restlessness seen in this type of melancholia.

This long tradition culminated, as with many other aspects of psychiatric nosology, in Kraepelin's careful descriptions [35]. He describes two forms of mixed depression.

Excited depression

It is here a case of patients who display on the one hand extraordinary poverty of thought but on the other hand great restlessness. They are communicative, need the doctor, have a great store of words, but are extraordinary monotonous in their utterances. Mood is anxious, despondent, lachrymose, irritable, occasionally mixed with a certain self-irony. The excitement of the patients also is usually not so stormy or protean. They run hither and thither, up and down, wring their hands, pluck at things, speak loud out straight in front of them, and give utterance to rhythmic cries.

Depression with flight of ideas

In the usual picture of depression inhibition of thought may be replaced by the flight of ideas…[the patients] cannot hold fast their thoughts at all, that constantly things come crowding into their head … in such cases we have to do with the appearance of a flight of ideas which only on account of the inhibition of external movements of speech is not recognizable … Occasionally the patients, who cannot give utterance to anything at all in speech, are capable of writing, and then compose to our astonishment comprehensive documents, often desultory, full of ideas of sin and delusional fears.’

Wilhelm Weygandt, who coined the term ‘agitated depression’ in his famous monograph on mixed states [36], considers agitated depression an association of depressed mood with psychomotor excitement and flight of ideas. He mentions elevated mood only in cases of a shift to pure or mixed manic/hypomanic states.

In the above-mentioned descriptions, the clinical picture of patients with mixed depression is clearly characterized by excitatory symptoms: motor agitation, anxiety, anguish, racing and crowded thoughts, irritability and rage. These symptoms were considered the core of depression with mixed features. In these classical authors, with two millennia of clinical experience, there is no mention of five of the seven symptoms (excluding pressured speech and flight of ideas) that are part of DSM-5 criteria for mixed features.

The evidence of science: mixed depression in the recent literature

In the DSM-5 website [25], the Mood Disorders Work Group gave details about the rationale for their proposal. Briefly, they acknowledged that a substantial proportion of subjects with a DSM-IV based diagnosis of major depressive episode (MDE), also present manic symptoms but insufficient in number to meet the DSM-IV definition of mixed episode. Specifically, in their review of recent research, they reported a frequency of patients with MDD with at least one manic symptom ranging from 22% to 50%, and with at least three manic symptoms ranging from 7% to 23%. Similar proportions were found among depressive bipolar I (BP I) and bipolar II (BPII) patients: more than half experienced at least one manic symptom, and 10–16% experienced at least three manic symptoms.

The Mood Disorders Work Group also accepted that mixed depressive patients are likely to belong to bipolar spectrum given the fact that, compared with MDD, they have an earlier age of onset, a greater number of episodes, more days with irritable or elevated mood in the preceding year, and a greater likelihood of past alcohol abuse, suicide attempts, past rapid cycling, and a lifetime diagnosis of bipolar disorder. Finally, they highlighted how DSM-IV definition of mixed state led to an under-detection of important clinical and therapeutic information.

The above rationale is based on data drawn from several papers published in the last decade [37-45].

We reviewed the same papers to find clinical descriptions of patients with mixed depression and to assess the type and frequency of manic/hypomanic symptoms during the depressive episodes.

Table 3 presents the reviewed articles and the main findings.

Table 3. Type and frequency of intradepressive ‘hypomanic/manic’ symptoms reported in the papers used as reference by DSM-5 Mood Disorder Work Group
AuthorAssessment toolsPopulationMost frequent ‘manic’ symptoms during MDE n (%)
  1. AMPD-system, Association for Methodology and Documentation in Psychiatry; BIS, Barratt Impulsiveness Scale; BPI, bipolar disorder, Type I; BPII, bipolar disorder, Type II; CPRS, Comprehensive Psychopathological Rating Scale; DMS, depressive mixed state; DMX3, MDE plus three or more concurrent ‘hypomanic’ signs and symptoms; GAF, Global Assessment of Functioning; IEMS, intraepisode manic symptoms; MADRS, Montgomery-Åsberg Depression Rating Scale; M-CIDI, Munich Composite International Diagnostic Interview; MDD (alias UP), major depressive disorder; MDE, Major depressive episode; MINI, Mini-International Neuropsychiatric Interview; n.r., not reported; RDC, Research Diagnostic Criteria; SADS, Schedule for Affective Disorders and Schizophrenia; SCID-CV, Structured Clinical Interview for DSM-IV Axis I Disorders-Clinical Version; UP (alias MDD), unipolar disorder; YMRS, Young Mania Rating Scale.

  2. a

    < 0.01.

  3. b

    MDD w/out any hypomanic features.

  4. c

    MDD w/ subthreshold hypomania.

  5. d

    Dysthymia, minor depression, or recurrent brief depression.

  6. e

    Dysthymia, minor depression, or recurrent brief depression with subthreshold hypomania.

  7. f

    Hypomania with or without dysthymia, minor depression, or recurrent brief depression.

  8. g

    Sample limited to 660 patients.

  9. h

    sample limited to 195 patients.

Sato et al. [37]ICD-10AMPD-SystemUP w/ depressive states = 863Motor restlessness 303 (35)
Irritability 125 (15)
Distractibility58 (7)
Racing thoughts54 (6)
Logorrhea49 (6)
BPII w/ depressive states = 25Racing thoughts/Flight of ideas5 (20)
Motor restlessness4 (16)
Irritability4 (16)
Distractibility3 (12)
Logorrhea/Increased drive2 (8)
BPI w/ depressive states = 70Motor restlessness20 (29)
Irritability12 (17)
Racing thoughts10 (14)
Distractibility10 (14)
Logorrhea8 (11)
Akiskal and Benazzi [38]SCID-CVHypomania Interview GuideUP w/ MDE = 151 (23.1% DMX3)BPII w/MDE = 226 (58.4% DMX3)Symptoms associated to DMX3(OR)an.r.
Psychomotor agitation30.5
Increased pleasurable activity26.5
More talkativeness11.7
Racing/crowded thoughts11.2
Sato et al. [39]ICD-10AMPD-SystemUP w/ depressive states = 149n.r.n.r.
Depressive pts w/ switch UP to BP = 24
BP w/ depressive states= 35
Maj et al. [40]SADSRDCCPRSMDD w/ agitated depression = 94Physically restless94 (100)
Irritable mood45 (47.9)
More talkative than usual27 (28.7)
Distractibility24 (25.5)
Flight of ideas/Racing thoughts16 (17)
MDD with non-agitated depression = 94Irritable mood 16 (17)
Distractibility8 (8.5)
Flight of ideas/Racing thoughts7 (7.4)
Physically restless6 (6.4)
More talkative than usual3 (3.2)
BPI depression = 94n.rn.r.
Swann et al. [41]SCIDSADSBISBP I/II with MDE = 56n.r.n.r.
Zimmermann et al. [42]M-CIDISCIDPure MDDb = 286n.r.n.r.
Subthreshold BPDc = 202
BP I = 65
BP II = 33
Pure mild depressiond = 171
Subthreshold minor BPDe = 125
Minor BPDf = 55
Controls = 1273
Goldberg et al. [43]MINIAffectiveDisordersEvaluationMADRSYMRSBP MDE w/out manic sx = 431None0
BP MDE w subsyndromal mania (1 to 3 sx) = 745Distractibility298 (40)
Irritable moodg262 (40)
Psychomotor agitation142 (19)
Flight of ideas/Racing thoughts119 (16)
Increased speech 37 (5)
Full Mixed Episode = 204Irritable moodh102 (53)
Distractibility 31 (15)
Flight of ideas/Racing thoughts 27 (13)
Psychomotor agitation 25 (12)
Increased speech 20 (10)
Fiedorowicz et al. [44]RDCSADS MDD MDE = 442+ BPI MDE = 41+ BPII MDE= 67None431 (78)
Increase in goal-directed activity65 (12)
Unusually energetic64 (12)
Elevated/expansive mood60 (11)
Grandiosity38 (7)
Less need for sleep (N.B. Data related to the whole sample)36 (7)
Angst et al. [45]DSM-IV-TR checklistMINIHypomania checklistDSM-IV-TR criteria definitionn.r.n.r.
MDE = 4732
BP MDE = 903
Bipolarity specifier definition
MDE = 2988
BP MDE = 2647

Five studies reported the type and frequency of intradepressive manic/hypomanic symptoms. Sato et al. [37] addressed directly the question. They recruited 958 in-patients (863 UP, 25 BP II and 70 BP I) with a current depressive episode (ICD-10 diagnoses: depressive episode F33.0: and bipolar affective disorder, current depressive episode F31.3–31.5). Over 100 psychiatric symptoms were assessed at admission and all patients were evaluated using the Association for Methodology and Documentation in Psychiatry (AMPD) system. In all three groups, the most frequent symptoms were motor restlessness, irritability, racing thoughts/flight of ideas, distractibility, and logorrhea. Euphoria and grandiosity ranged from 1% (4–6 of 863 unipolar patients) to 4% (1 of 25 bipolar II patients), excessive social contact from 1% (7 of 863 unipolar patients) to 4% (1 of 25 bipolar II patients), and increased drive (energy) from 5% (44 of 863 unipolar patients) to 9% (6 of 70 bipolar I patients). In the discussion section, the authors clearly stated that ‘euphoria and grandiosity were too rare in our depressed patients to be utilized for the selection of patients with depressive mixed states’.

Akiskal and Benazzi [38] presented a systematic clinical description of 337 patients with MDE (BPII = 226, UP = 151). The patients were assessed using the Structured Clinical Interview for DSM-IV Axis I disorder–Clinical Version (SCID-CV). The authors used the definition of depressive mixed state (DMX) as a major depressive episode (MDE) plus at least three (DMX3) concurrent hypomanic signs and symptoms. A logistic regression was used to study associations. As far as clinical hypomanic symptoms are concerned, DMX3 was significantly (< 0.01) associated only with irritability, increased pleasurable activity, psychomotor agitation, distractibility, more talkativeness, and racing/crowded thoughts.

Maj et al. [40] conducted a study on Research Diagnostic Criteria (RDC)-diagnosed agitated depressive patients compared with a sample of patients with non-agitated major depressive disorder and one of patients with bipolar I depression. All patients were assessed with the Comprehensive Psychopathological Rating Scale (CPRS). Apart from the predictable significant differences in terms of frequency, both the agitated and non-agitated depressive patient groups present the same most frequent hypomanic symptoms: physical restlessness, irritable mood, more talkativeness, distractibility, and racing thought/flight of ideas. The authors found no depressive patients, either agitated or non-agitated, with elevated mood, inflated self-esteem or grandiosity, decreased need for sleep, hyperactivity socially or at work. The symptom of ‘excessive involvement in activities with potential painful consequences’ was slightly more frequent in the agitated group, but the absolute rates were very small (3.2% vs. 0%, = 0.08).

Goldberg et al. [43] analyzed the data of 1380 affective patients [BP MDE without manic symptoms = 431, BP MDE with subsyndromal mania (one to three manic symptoms) = 745, full mixed episode = 204], selected from 4107 enrollees in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Distractibility, irritable mood, psychomotor agitation, racing thoughts, and increased speech were the most frequently identified manic symptoms in this large sample of bipolar patients with MDE. The authors stated that

it is noteworthy that the specific manic symptoms with the highest frequency in bipolar patients in depressed episodes … do not include either elation or grandiosity. This suggests that the DSM-IV-TR “B” criteria for mania may, unintentionally, serve to reduce recognitions of manic symptoms in bipolar depressed patients.

Fiedorowicz et al. [44] screened 550 patients with MDD diagnosis according to RDC. At the end of the follow-up period (mean duration = 17.5 years), diagnostic change from MDD to BP was observed in 108 patients (BPI = 41, BPII = 67). All patients were assessed at baseline for five manic symptoms (elevated mood, less need for sleep, unusually energetic, increased goal-directed activity, and grandiosity) using the Schedule of Affective Disorders and Schizophrenia (SADS). Patients were not uniformly screened for other symptoms of mania. In the whole group, these manic symptoms, similar to the DSM-5 criteria, only ranged from 7% to 12%.

In summary, five of seven papers used as reference by DSM-5 Mood Disorders Work Group addressed the issue of phenomenology of mixed depressive states. In three of them [37, 40, 43], the authors did not find any of the proposed DSM-5 symptoms as diagnostically relevant for identifying depression with mixed features. In fact, Sato et al. [37] decidedly affirmed that euphoria and grandiosity, the first two diagnostic criteria proposed by DSM-5, were too rare to be considered diagnostically important in mixed depressive clinical pictures. Where DSM criteria were observed, like clear hypomanic symptoms [44], they were infrequent (occurring in only 7–12% of depressive patients).

Other studies not included in the DSM-5 task force report

Table 4 presents the other papers reviewed in our overview of the literature.

Table 4. Type and frequency of intradepressive ‘hypomanic/manic’ symptoms reported in the papers that addressed the phenomenology of mixed depression
AuthorAssessment toolsPopulationMost frequent ‘manic’ symptoms during MDE n (%)
  1. AMPD-system, Association for Methodology and Documentation in Psychiatry; BPI, Bipolar disorder, Type I; BPII, Bipolar disorder, Type II; MDD (alias UP), Major depressive disorder; MDE, Major depressive episode; MINI, Mini-International Neuropsychiatric Interview; MOODS-SR, Mood Spectrum Self-Report Instrument; n.r., not reported; OPCRIT, Operational Criteria for Psychotic Illness checklist; OR, Odds ratio; RDC, Research Diagnostic Criteria; SADS, Schedule for Affective Disorders and Schizophrenia; SCID, Structured Clinical Interview for DSM-IV Axis I Disorders; UP (alias MDD), Inipolar disorder; YMRS (or MRS), Young Mania Rating Scale.

  2. a

    Factors independently associated with agitated depression indentified by a logistic regression analysis.

Perlis et al. [46]Psychiatric Diagnosis Screening Questionnaire (self report)DSM-IV-TR 2397 MDDInvolvement360 (15.0)
Talkativeness356 (14.9)
Impulsivity342 (14.3)
Cheerfulness279 (11.6)
Confidence249 (10.4)
Increased energy/decreased sleep171 (7.1)
Judd et al. [47]DSM-IV-TRRDCSADS142 BP MDEIrritability81 (57.0)
Psychomotor agitation56 (39.4)
Elevated mood19 (13.4)
Heightened energy16 (11.3)
Increased goal-directed activity14 (9.9)
Less need for sleep than usual12 (8.5)
Flight of ideas or racing thoughts11 (7.7)
Talkativeness9 (7.7)
Distractibility9 (6.3)
Inflated self-esteem7 (4.9)
Risk-taking behaviour2 (1.7)
Pae et al. [48]DSM-IV-TRSCIDMRS72 (BPII+MDD) MDEFlight of ideasn.r. (60)
Irritabilityn.r (59)
Distractibilityn.r. (58)
Decreased need for sleepn.r. (44)
Thoughtlessnessn.r. (28)
Pressured speechn.r. (24)
Increased activityn.r. (22)
Grandiosityn.r. (14)
Bertschy et al. [51]MINIDSM-IV- TR165 Manic or DepressiveDysphoria (inner tension, irritability, aggressive behaviour, hostility)MDE n.r. (17.5)
Mania n.r. (22.7)
Full mixed state n.r. (73.3)
Olgiati et al. [52]DSM-IV-TRNIMH Life ChartsOPCRIT314 MDDDysphoriaORa
Delusion and hallucinations lasting for 1 week2.25 (p<.001)
Reduced need for sleep6.21 (p.008)
6.26 (p.04)
Benazzi [49]SCIDHypomania Interview Guide245 BPII MDEDistractibilityn.r. (84.3)
Racing/crowded thoughtsn.r. (76.1)
Irritable moodn.r. (59.2)
Psychomotor agitationn.r. (41.1)
Increased Risky activities n.r. (25.1)
More talkativenessn.r. (23.8)
Increased goal-directed activityn.r. (9.4)
Reduced need for sleepn.r. (0.8)
Increased self esteemn.r. (0)
Elevated moodn.r. (0)
189 MDD MDEDistractibilityn.r. (77.7)
Racing/crowded thoughtsn.r. (58.7)
Irritable moodn.r. (39.6)
Psychomotor agitationn.r. (26.4)
More talkativenessn.r. (11.1)
Increased risky activities n.r. (11.1)
Increased goal-directed activity n.r. (2.1)
Reduced need for sleepn.r. (0)
Increased self esteemn.r. (0)
Elevated moodn.r. 0)
Akiskal et al. [50]SCIDHypomania Interview Guide50 MDD agitatedDistractibilityn.r. (86)
Racing/crowded thoughtsn.r. (74)
Irritable moodn.r. (52)
Talkativenessn.r. (36)
Increased risky activitiesn.r. (18)
Increased goal-directed activityn.r.
Reduced need for sleepn.r. (0)
Increased self esteemn.r. 0)
Elevated moodn.r. (0)
  254 MDD not agitatedDistractibilityn.r. (62.2)
Racing/crowded thoughtsn.r. (51.4)
Irritable moodn.r. (33.8)
Talkativenessn.r. (3.9)
Increased risky activitiesn.r. (5.8)
Increased goal-directed activityn.r.
Reduced need for sleepn.r. (0)
Increased self esteemn.r. (0)
Elevated moodn.r. (0)
Sato et al. [53]AMPD-system958 MDDHypomanic symptoms isolated as an independent factorLoad
Flight of ideas0.667
Excessive social contact0.538
Increased drive0.485
Racing Thoughts0.403
Maj et al. [54]DSM-IV-TR RDC61 BPI MDE agitatedIncreased motor activity61 (100.0)
Pressured speech25 (41.0)
Racing thoughts18 (29.5)
61 BPI MDERacing thoughts2 (3.3)
Pressured speech2 (3.3)
Increased motor activity3 (4.9)
61 BPI ManiaIncreased motor activity 59 (96.7)
Pressured speech57 (93.4)
Racing thoughts36 (59.0)

Perlis et al. [46], analyzing data from the STAR*D study, assessed the presence of mixed features among 2397 patients with MDD. They used a modified version of the Psychiatric Diagnosis Screening Questionnaire (PDSQ). These patients showed involvement (15.0%), talkativeness (14.9%), impulsivity (14.3%), cheerfulness (11.6%), confidence (10.4%), increased energy/decreased sleep (7.1%).The authors found an ‘association between proposed DSM-5 mixed features and a greater likelihood of remission’.

Judd et al. [47] reported the frequency of subsyndromal manic symptoms, rated using a modified version of the SADS interview, among 142 subjects with bipolar depression. The most frequent symptoms found were irritability (57%), psychomotor agitation (39.4%), elevated mood (13.4%), flight of ideas or racing thoughts (11.3%), and distractibility (9.9%).

Pae et al. [48] found flight of ideas (60%), irritability (59%), distractibility (58%), as the most common symptoms among 72 patients with mixed depression. These results are in line with those previously found by other authors [49, 50].

Dysphoria, defined as a constellation of symptoms such as inner tension, irritability, aggressive behaviour and hostility, was ascertained in 73.3% of patients with a mixed state [51]. Similarly, Olgiati et al. [52] found that dysphoria, together with psychotic symptoms and reduced need for sleep, was an independent predictor of agitated depression in a multivariate model.

Sato et al. [53] carried out a factor analysis of 43 symptoms including a broad range of depressive as well as hypomanic symptoms, systematically assessed using a standardized method in 958 patients with acute depression. They found that a specific factor isolated the following symptoms: flight of ideas, logorrhea, aggression, excessive social contact, increased drive, irritability, and racing thoughts. They, also, noted that symptoms representative of classic mania – such as euphoria, grandiosity, and distractivity – did not have high loading on this factor.

In a previous study, Maj et al. [54] assessed 61 patients with agitated depression selected from 313 patients with Bipolar I depression. These patients showed physical restlessness (100%), irritable mood (50.8%), talkativeness (41%), distractibility (32.8%), and racing thoughts (29.5%). All patients had depressed mood. Not a single patient was described as having elevated mood or inflated self-esteem.

Finally, we examined 212 patients with mixed depression, and we reported that the most frequent symptoms were absence of retardation (82%), talkativeness (70%), mood lability (55%), racing/crowded thoughts (54%), dramatic description of suffering (52%), irritability (48%), and early insomnia (35%) (unpublished data).

In sum, the other studies reviewed, with the exception of one paper [45], provide additional scientific evidence to support the potential validity of our hypothesis, and the clinical utility of using a different set of symptoms, other than DSM-5 criteria, to characterize mixed depression.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

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 [35], 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 [55], Thalbitzer [56], and also Dreyfus [57] 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 [58] 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 [59] 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’ [59].

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. [48], 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 [63] 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.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References
  • 1
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 1st edn. Washington: American Psychiatric Association, 1952.
  • 2
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 2nd edn. Washington: American Psychiatric Association, 1968.
  • 3
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd edn. Washington: American Psychiatric Association, 1980.
  • 4
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd edn, rev. Washington: American Psychiatric Association, 1987.
  • 5
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edn. Washington: American Psychiatric Association, 1994.
  • 6
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edn - Text Revision. Washington: American Psychiatric Association, 2000.
  • 7
    Frances A. DSM in philosophyland: curioser and curioser.; 2010 [cited 2010 November 8]; Available from:
  • 8
    Frances A. Whither DSM-V? Br J Psychiatry 2009;195:391392.
  • 9
    Shorter E. Before Prozac: the troubled history of mood disorders in psychiatry. New York: Oxford University Press, 2009.
  • 10
    Spitzer RL, Endicott J, Robins E. Research diagnostic criteria (RDC). New York: Biometrics Research, Evaluation Section, New York State Psychiatric Institute, 1978.
  • 11
    Koukopoulos A, Faedda G, Proietti R, D'Amico S, de Pisa E, Simonetto C. Mixed depressive syndrome. Encephale 1992;18:1921.
  • 12
    Koukopoulos A, Koukopolos A. Agitated depression as a mixed state and the problem of melancholia. Psychiatr Clin North Am 1999;22:547564.
  • 13
    Akiskal HS. The distinctive mixed states of bipolar I, II, and III. Clin Neuropharmacol 1992;15:632A633A.
  • 14
    Benazzi F. Depressive mixed states: unipolar and bipolar II. Eur Arch Psychiatry Clin Neurosci 2000;250:249253.
  • 15
    Bourgeois M, Verdoux H, Mainard CH. Dysphoric mania and mixed states. Encephale 1995;21:2132.
  • 16
    Dell'Osso L, Placidi GF, Nassi R, Freer P, Cassano GB, Akiskal HS. The manic-depressive mixed state: familial, temperamental and psychopathologic characteristics in 108 female inpatients. Eur Arch Psychiatry Clin Neurosci 1991;240:234239.
  • 17
    Himmelhoch JM, Coble P, Kupfer KJ, Ingenito J. Agitated psychotic depression associated with severe hypomanic episodes: a rare syndrome. Am J Psychiatry 1976;133:765771.
  • 18
    Perugi G, Akiskal HS, Micheli C et al. Clinical subtypes of bipolar mixed states: validating a broader European definition in 143 cases. J Affect Disord 1997;43:169180.
  • 19
    Koukopoulos A, Girardi P, Proietti R, Gaston A. Diagnostic and therapeutic considerations on agitated depression understood as a mixed affective state. Minerva Psichiatr 1989;30:283286.
  • 20
    Swann AC, Secunda SK, Katz MM et al. Specificity of mixed affective states: clinical comparison of dysphoric mania and agitated depression. J Affect Disord 1993;28:8189.
  • 21
    Koukopoulos A, Sani G, Koukopoulos AE, Manfredi G, Pacchiarotti I, Girardi P. Melancholia agitata and mixed depression. Acta Psychiatr Scand Suppl 2007;433:5057.
  • 22
    Pacchiarotti I, Nivoli A, Mazzarini L et al. The symptom structure of a bipolar acute episodes: in search for the mixing link. J Affect Disord 2013;149:5666.
  • 23
    Lange J. Die endogenen und reaktiven Gemuetserkrankugen und die manische-depressive Konstitution. In: Bumke O, ed. Handbuch Der Geisteskrankheiten, 6. Berlin: Verlag Von Julius Springer, 1928:110121.
  • 24
    Koukopoulos A, Sani G, Albert MJ, Minnai GP, Koukopoulos AE. Agitated depression: spontaneous and induced. In: Goodwin FK, Marneros A, eds. Mixed states, rapid cycling and atypical bipolar disorders. London: Cambridge University Press, 2004:157186.
  • 25
    DM5 web site, available at: (last access: October 2012)
  • 26
    Hippocrates. Diseases II: para. 72. Cambridge, Massachusetts: Harvard University Press, 1988.
  • 27
    Aretaeus. De Causis et Signis de Morborum. Lugduni Batavorum: J. Vander, 1735.
  • 28
    Ibn Imran I. Traite de la melancolie (translated by Omrani). Carthage: Academie tunisienne des Science, des Lettres et des Arts, Beit al-Hikma, 2009.
  • 29
    Heinroth JCA. Lehrbuch der Stoerungen des Seelenlebens. Leipzig: Vogel, 1818.
  • 30
    Rush B. Medical inquiries and observations upon the diseases of the mind, 4th edn. Philadelphia: John Grigg, 1830.
  • 31
    Griesinger W. Pathologie und Therapie der psychischen Krankheiten. Stuttgart: Adolf Krabbe Verlag, 1845.
  • 32
    Farlet JP. Leçons Cliniques de Médecine Mentale. J.B. Baillière ed, Paris, 1854.
  • 33
    Baillarger J. Note sul un genre di folie don't les accés sont caractérisée par l'alternative régulière de la manie et de la mélancolie. Bull. Acad. Méd. XIX, 340, Ann. Méd. Psychol. XII, 1854.
  • 34
    Richarz F. Ueber Wesen und Behandlung der Melancholie mit Aufregung (Melancholia agitans). Allg Ztschr Psychiatr 1858;15:2865.
  • 35
    Kraepelin E. Psychiatrie, ed 8. JA Barth ed, Leipzig, 1913.
  • 36
    Weygandt W. Ueber die Mischzustaende des manisch-depressiven Irreseins. Muenchen: Lehmann, 1899.
  • 37
    Sato T, Bottlender R, Schroter A, Moller HJ. Frequency of manic symptoms during a depressive episode and unipolar ‘depressive mixed state’ as bipolar spectrum. Acta Psychiatr Scand 2003;107:268274.
  • 38
    Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 2003;73:113122.
  • 39
    Sato T, Bottlender R, Sievers M, Schroter A, Kleindienst N, Moller HJ. Evaluating the inter-episode stability of depressive mixed states. J Affect Disord 2004;81:103113.
  • 40
    Maj M, Pirozzi R, Magliano L, Fiorillo A, Bartoli L. Agitated “unipolar” major depression: prevalence, phenomenology, and outcome. J Clin Psychiatry 2006;67:712719.
  • 41
    Swann AC, Moeller FG, Steinberg JL, Schneider L, Barratt ES, Dougherty DM. Manic symptoms and impulsivity during bipolar depressive episodes. Bipolar Disord 2007;9:206212.
  • 42
    Zimmermann P, Bruckl T, Nocon A et al. Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity. Arch Gen Psychiatry 2009;66:13411352.
  • 43
    Goldberg JF, Perlis RH, Bowden CL et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry 2009;166:173181.
  • 44
    Fiedorowicz JG, Endicott J, Leon AC, Solomon DA, Keller MB, Coryell WH. Subthreshold hypomanic symptoms in progression from unipolar major depression to bipolar disorder. Am J Psychiatry 2011;168:4048.
  • 45
    Angst J, Azorin JM, Bowden CL et al. Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch Gen Psychiatry 2011;68:791798.
  • 46
    Perlis RH, Cusin C, Fava M. Proposed DSM-5 mixed features are associated with greater likelihood of remission in out-patients with major depressive disorder. Psychol Med 2012;15:17.
  • 47
    Judd LL, Schettler PJ, Akiskal H et al. Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes. J Affect Disord 2012;138:440448.
  • 48
    Pae CU, Vöhringer PA, Holtzman NS et al. Mixed depression: a study of its phenomenology and relation to treatment response. J Affect Disord 2012;136:10591061.
  • 49
    Benazzi F. Family history validation of a definition of mixed depression. Compr Psychiatry 2005;46:159166.
  • 50
    Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord 2005;85:245258.
  • 51
    Bertschy G, Gervasoni N, Favre S et al. Frequency of dysphoria and mixed states. Psychopathology 2008;41:187193.
  • 52
    Olgiati P, Serretti A, Colombo C. Retrospective analysis of psychomotor agitation, hypomanic symptoms, and suicidal ideation in unipolar depression. Depress Anxiety 2006;23:389397.
  • 53
    Sato T, Bottlender R, Kleindienst N, Möller HJ. Irritable psychomotor elation in depressed inpatients: a factor validation of mixed depression. J Affect Disord 2005;84:187196.
  • 54
    Maj M, Pirozzi R, Magliano L, Bartoli L. Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome. Am J Psychiatry 2003;160:21342140.
  • 55
    Specht G. Ueber die Strukture und klinische Stellung der Melancholia agitata. Zentralbl Nervenheilkr Psych 1908;39:449469.
  • 56
    Thalbitzer S. Die manisch-depressive Psychose: das Stimmungs-irresein. Arch Psychiatr Nervenkr 1908;43:10711127.
  • 57
    Dreyfus GL. Die Melancholie, ein Zustandsbild des manisch-depressiven Irreseins. Jena: G. Fischer, 1907.
  • 58
    Westphal A, Koelpin O. Bemerkungen zu dem Aufsatze von Prof. Dr. G. Specht: Ueber den Angstaffekt im manisch-depressiven Irresein. Zentralbl Nervenheilkr Psychiatrie 1907;18:729731.
  • 59
    Griesinger W. Pathologie und Therapie der psychischen Krankheiten, 2nd edn. Stuttgart: Adolf Krabbe Verlag, 1861.
  • 60
    Koukopoulos A, Albert MJ, Sani G, Koukopoulos AE, Girardi P. Mixed depressive states: nosologic and therapeutic issues. Int Rev Psychiatry 2005;17:2137.
  • 61
    Sani G, Tondo L, Koukopoulos A et al. Suicide in a large population of former psychiatric inpatients. Psychiatry Clin Neurosci 2011;65:286295.
  • 62
    Pacchiarotti I, Mazzarini L, Kotzalidis GD et al. Mania and depression. Mixed, not stirred. J Affect Disord 2011;133:105113.
  • 63
    Maj M. Mixed states and rapid cycling: conceptual issues and options for ICD-11. World Psychiatry 2012;11(Suppl. 1):6568.