Agitated Depression as a mixed state

Agitated Depression as a mixed state and the problem of melancholia

Authors: Koukopoulos At, Koukopoulos Al
Psychiatr Clin North Am - 01-Sep-1999; 22(3): 547-64
1 Centro Lucio Bini (AtK)
2 University of Rome La Sapienza, (AlK), Rome, Italy

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"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 underly 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 suffering." (Wilhelm Griesinger, 1981) [26]

Today's extensive use of antidepressant drugs in the treatment of all forms of depression makes the question of the real nature of agitated depression a critical issue. Many of these patients are seen to have such adverse outcomes as increased agitation, intractable panic, heightened risk of suicide, manifestation of psychotic symptoms, and worsening of the subsequent course of the illness. [20] [36] There is a noticeable gap between the proven efficacy of antidepressant drugs and the eventual outcomes of treated depressed patients. The failure to recognize agitated depression as a mixed state may be responsible for some of these disappointing outcomes. This article traces the evolution of the concepts of melancholia, depression, and mixed states. The psychopathology of agitated depression as a mixed state, its clinical forms, and how they differ from major depression are discussed. New diagnostic criteria are proposed for agitated depression, covering all of its clinical varieties.

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MELANCHOLIA
From classical antiquity to the end of the nineteenth century, melancholia was described in various forms, many of which would today be considered mixed affective states. The first and one of the best descriptions of agitated melancholia is found in Hippocrates, 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. [31]

As Toohey [69] points out, Aristotle [8] in his XXX Problema cited as melancholic both Heracles, [21] who kills his sons in a fit of fury, and Ajax, [63] who, in an awesome rage, slaughters the cattle in the mistaken belief that he is taking his revenge on Ulysses, Agamemnon, and Menelaus. Aretaeus [7] stated that melancholics suffer from "violent rage and sadness and awful dejection." The nosologists of the eighteenth century, such as de Sauvages [10] and Cullen, [17] classified among the melancholias such forms as melancholia phrontis, melancholia moria, melancholia saltans, melancholia errabunda, melancholia silvestris, melancholia furens, and melancholia enthusiastica.

Heinroth [28] abandoned the intellectualistic conception of melancholia and considered it a disease of the mood (Gemu th). In his classification of the morbid conditions of the soul, he placed melancholia metamorphosis among states of exaltation (hypersthenia), whereas among the manias he listed melancholia saltans. Among the mixtures of exaltation with weakness (hyperasthenia), he cited ecstasis melancholica, melancholia furens, mania melancholica, and athymia melancholico-maniaca (timidity with melancholia and rage).

Griesinger [25] considered melancholia a disease of the affects (intense, altered emotional states), distinguishing them into two major classes: the expansive, affirmative ones, such as happiness, joy, and hope, and the depressive, negative ones, such as dejection, sadness, and fear. He placed rage in an intermediate position between the two kinds of affects. Griesinger described, among the states of mental depression, melancholia in the strict sense, melancholia with destructive tendencies, and melancholia with persistent excitement of the will. As noted earlier, he had the great insight that processes of cerebral excitation may be the cause of psychic pain and depression. Griesinger saw the cause of melancholia in a state of hyperesthesia, and Kahlbaum [34] saw the cause in a state of hyperthymia. As Schmidt-Degenhardt [59] points out, there is an evident contrast with the concept of depression, which implies a suppression or weakening of brain processes. The first to use the term melancholia agitans was Richarz [56] in 1858. More commonly termed as melancholia agitata, it was widely employed in the second half of the nineteenth century, and it was later replaced by Angstmelancholie and eventually agitated depression.

With the introduction of Folie Circulaire by Falret [22] in 1851, a significant

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number of melancholias became a component of a more complex disease entity and lost their nosologic independence. This nosographic evolution led eventually to the creation of manic-depressive insanity by Kraepelin [43] in 1899 and the definitive substitution of the concept of melancholia with that of depression. Many psychiatrists had proposed substituting the term melancholia, which had become too vague, with other terms such as tristimania, [57] lypemania, [20] dysthymia, [23] and vecordia melaena. [34]

In the first edition (1883) of his textbook, Kraepelin [38] placed melancholia activa among the excited states and distinguished it from melancholia periodica, which is in any case marked by delirious or delusional ideas and anxious agitation. Only melancholia of circular insanity, marked by psychic and physical inhibition, corresponds to the clinical picture of the present disorder major depression. In the second (1887) [39] and third (1889) [40] editions, Kraepelin distinguished between melancholia activa, very agitated, and melancholia simplex. In the fourth edition (1893), [41] he replaced melancholia activa with Angstmelancholie, to emphasize better the anxiety component of this condition. In the fifth edition (1896), [42] he introduced melancholia of the age of involution: "with the name of melancholia we designate all pathological anxious depressions of older age which do not represent parts in the course of other psychic disorders." The clinical picture also comprised delusions, especially of guilt but also of persecution, and hypochondriacal ideas. The similarity to the old melancholia agitata is evident. He included Angstmelancholie in involutional melancholia.

In the eighth edition (1913), [45] Kraepelin subsumed involutional melancholia into manic-depressive insanity, accepting the results of the catamnestic investigation carried out by his student Dreyfus (1907) [19] on Kraepelin's same patients in Heidelberg. In essence, Dreyfus showed that involutional melancholia was a mixed state of manic-depressive insanity. In his foreword to Dreyfus's Melancholia, Kraepelin wrote with evident regret: "Nevertheless, it is to be foreseen that the old clinical form of Melancholia, one of the oldest in psychiatry, will completely disappear because it contains mainly manic-depressive features." What he could not have foreseen was that by the end of the twentieth century, agitated depression, which had replaced melancholia, in all likelihood would also disappear as a mixed state.

In the following decades, the concept of melancholia was replaced, in European psychiatry, by the concept of endogenous depression and in the United States by the concept of depressive reaction according to Meyer's [52] idea of reaction types. Under the impact of the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III), [4] the term major depression replaced worldwide the terms of melancholia, endogenous depression, and depressive reaction. The term involutional melancholia remained in use for a long time, and it was still present in the DSM-II. [3] It was abandoned as the name of a separate entity in the DSM-III, and the term melancholia was relegated to a subclassification at the fifth digit: Major Depressive Episode with Melancholia: "a term from the past in this manual used to indicate a typically severe form of depression that is

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particularly responsive to somatic therapy." This subclassification may be seen as an effort to preserve the oldest term in psychiatry. Certainly the syndrome described here would have been called melancholia simplex in the past, but it does not bring out the dramatic picture of anxiety, fear, rage, and delusional ideas that have traditionally been associated with the term melancholia and are still seen in clinical practice today. The term melancholia would have better suited the form described as Major Depressive Episode with Psychotic Features.

Another key shift in the DSM III was the introduction of the term bipolar disorder in place of manic-depressive illness. In this regard, the authors fully share Jamison's [32] view: "the word `bipolar' seems to me to obscure and minimize the illness it is supposed to represent (...) and it minimizes the importance of mixed manic and depressive states, conditions that are common, extremely important clinically, and lie at the heart of many of the critical theoretical issues underlying this particular disease."

MIXED STATES
Many authors clearly described mixed states well before Kraepelin, including Lorry, [48] mania melancholica; Heinroth, [28] melancholia mixta catholica, melancholia furens; Guislain, [27] me lancholie maniaque; and Griesinger, [25] melancholia with persistent excitement of the will. Kraepelin conceptualized and described mixed states in a systematic way. He made them the cornerstone of the manic-depressive entity. In conceiving the manic-depressive mixed states, Kraepelin started from the excitement or depression of the three domains of psychic life: the intellect (train of thought rather than its contents), mood, and volition, expressed in psychomotor activity.

Distinguishing between the foregoing three domains of psychic life has been a constant idea in Western culture and stems both from Plato's [54] three elements of the soul--rational, emotional, and appetitive--and from Aristotle's [9] psychic powers (faculties)--rational, sensory, and appetitive. Via the equivalent faculties of Kant [35] --the rational, the sense of pleasure or pain, and the appetitive faculty--these distinctions have had a great influence on psychiatry and the understanding and classification of psychic disorders as well as the conception of mixed manic disorders in particular, as discussed later.

In the fifth edition of his textbook (1896), Kraepelin [42] introduced the concept of mixed states and described manic stupor. In the sixth edition (1899), [43] he presented the entity of manic-depressive insanity and described the mixed states: mania with inhibition of thought, manic stupor, querulous mania, states of transition, and depression with flight of ideas. In the seventh edition (1904), [44] he introduced among the mixed states depressive agitation and mania with poverty of ideas.

In the eighth edition of his textbook (1913), starting from mania, which consists of flight of ideas, exalted mood and hyperactivity,

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Kraepelin described depressive or anxious mania. Flight of ideas is evident in the speech of the patient, who continuously spins out thoughts and often shows a real passion for writing. The mood is anxiously despairing and is manifested in great restlessness and senseless pressure of activity. Ideas of sin and persecution or hypochondriacal delusions are frequently present. The amount of excitement in this condition is such that the noun mania seems appropriate, and, given the prominence of anxiety, the adjective anxious seems more suitable than depressive. This syndrome certainly comes close to the old melancholia agitata. The next mixed state is excited depression (erregte Depression) with inhibition of thought, great restlessness, and anxious and despondent mood. The difference between these two syndromes is flight of ideas in the first and inhibition in the second.

Although the foregoing two mixed forms originate, according to Kraepelin, from a manic state, the third one originates from a state of depression and is called depression with flight of ideas: "in a usual picture of depression, inhibition of thought may be replaced by flight of ideas ... They cannot hold fast their thoughts at all; constantly things come crowding into their heads." Kraepelin also states: "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 recognisable. The patients are almost mute and are rigid in their whole conduct and are of cast-down and hopeless mood." As discussed later, in many cases there is, in fact, no inhibition at all. The patient moves and talks freely and complains about crowded thoughts, whereas the mood is despondent. These two kraepelinian mixed states seem similar to the present agitated depression and are discussed later.

In 1888, Clouston [15] from Edinburgh described excited motor melancholia, a term that stresses the excitatory nature of the agitation. In 1899, a monograph appeared on Mixed States of Manic Depressive Insanity by Kraepelin's pupil Weygandt, [73] based on a study carried out in Heidelberg. He focused only on three types of mixed state: manic stupor, unproductive mania, and agitated depression. This is the first time to the authors' knowledge that the term agitated depression was used. Weygandt pointed out the similarity with agitated forms of involutional melancholia and, similar to Lange, [46] Specht, [64] and Thalbitzer, [68] considered melancholia agitata a mixed state of manic-depressive insanity, in contrast with Wernicke's [71] school of thought, which viewed it as a form of anxiety psychosis.

Stransky, [66] in 1911, wrote in Aschaffenburg's Handbook that the anxiety of melancholia agitata, or depression with anxious excitation, does not contain mixed elements. He also remarked that inhibition of thought is not always present in manic stupor, and motor inhibition does not affect facial expressiveness. He did not consider dysphoric mania a mixed state because the basic mood is an expansive one.

In 1928, Lange [46] discussed mixed states and said that classic, pure clinical pictures of mania or depression are rarely found. He recognized melancholia agitata as a mixed state. Among the mixed states, he described

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a form that he named excitable depression (anregbare Depression), marked by inner anxiety and lack of motor agitation. Some patients present with inhibition of thought, and some have flight of ideas. If they are somehow stimulated, these patients show motor agitation and exaggerated expressive movements. Lange pointed out that in many patients depressive mood and motor inhibition coexist with hyperactivity of thought.

Interest in mixed states was waning by the 1920s. In 1923, Jaspers [33] wrote that the issue of mixed states "did not have any further development, and this was very natural since elements of understanding psychology had been considered as objective components and factors of psychic life." Schneider [60] was more hasty: "We no longer believe in manic-depressive mixed states. Anyway, what may look like this is a change or a switch, if it pertains to Cyclothymia at all."

On purely psychopathologic grounds, without any knowledge of the underlying neuropathologic alterations, it is hard to make any progress in this field. The present interest in mixed states is due to the adverse effects of antidepressants and the beneficial effects of new anticonvulsant mood stabilizers, which seem to act on the underlying pathophysiology.

At present, agitated depression has lost its status as a mixed state, not only in the DSM system, but also in the view of most psychiatrists worldwide. Apart from the impact of the conceptual shifts that are mentioned subsequently, another reason may be the great efficacy of electroconvulsive therapy (ECT) in both agitated and retarded depression. The nosologic differences between the two forms were probably overshadowed by the similar therapeutic outcome. ECT is more effective on agitated depression than on any other form of depression. [37] ECT is effective in both mania and depression. [62] Agitated depression was considered a subtype of major depressive disorder in the Research Diagnostic Criteria (RDC) [65] but was not carried over in the DSM-III-R [5] or the DSM-IV. [6]

In the criteria of major depressive episode, agitation is listed as the fifth symptom: "psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). [6] " Over the course of more than 2000 years, the disease entity melancholia has become the syndrome agitated depression and now a symptom, agitation, of a depressive episode. This evolution has had an enormous impact on therapeutic approaches to depression. The kind of treatment is actually determined by the diagnosis of a disease or a syndrome and less by a symptom. Thus, major depressive episodes with or without agitation are treated in the same way, and the result is disastrous in many cases of agitated depression. Both symptoms and course worsen.

A significant inverse symmetry may be seen in the evolution that occurred with the concept of depression. In the beginning, it was a symptom that could be present in many conditions. Ziehen [74] objected to the term manic-depressive insanity on the grounds that Kraepelin had

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conflated a disease, mania, with a symptom, depression, and he proposed, as many others did, the term manic-melancholic insanity. Then, in the entity manic-depressive insanity, depression became a syndrome, the depressive phase of the illness. Today, depression is understood as a morbid entity and every physician is entitled to offer antidepressant treatment to nearly all patients with despondent mood diagnosed to meet the DSM-III criteria for a major depressive episode with or without agitation. Agitated depression is not considered a mixed state in DSM-IV or in International Classification of Diseases. Most psychiatrists [14] today consider it a form of depression with anxiety.

In recent years, a growing number of psychiatrists [1] [11] [18] [29] [36] [49] [53] [67] have expressed disenchantment with the official view, proposing agitated depression as a mixed form of affective disorders. The DSM system opposes this view because agitated depressives do not simultaneously meet the criteria for mania and major depression. Schatzberg [58] finds

... a number of key differences in the seeming overlap of symptoms: manic or mixed patients demonstrate a decreased need for sleep while agitated depressives complain of insomnia. The bipolar patient has increased thinking and increased speech, while agitated depressives have especially depressive ruminations and decreased speech. The increased motor activity of the agitated depressive is purposeless and unpleasant, while in bipolar patients it is often aimed at some grandiose goal.

One could object that the state of depression inevitably modifies the manic symptoms. The DSM system not only conceives a mixed state as an overlap of manic and depressive symptoms, but also requires the impossible simultaneous presence of a full manic and a full depressive syndrome.

The symptoms of agitated depression are of a different kind and, as explained later, arise from the reaction of an excitable temperament to a depressive episode. The current interest in this topic stems from the clinical observation that antidepressant drugs exacerbate agitation, insomnia, anxiety, and suicidal ideas in these patients. [2A] [36]

THE PARALLELISM BETWEEN DRIVE, MOOD, AND THOUGHT
Normal human behavior and especially behavior during affective episodes have created the impression that good mood is allied with good drive and fluent thinking and vice versa. Hypomania with euphoric mood and depression with retardation are typical examples of this parallelism. Cullen, [16] who ascribed the state of excitement and state of collapse (asthenia, depression) to changes in nervous power, said that "these different states of the brain are expressed in the body by strength or debility, alacrity or sluggishness; and in the mind by courage or timidity, gaiety or sadness."

This bipolarity is certainly a clinical reality, and the mixture of

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elements of excitement with elements of depression (inhibition) creates clinical pictures called mixed states. These elements are symptoms and these clinical pictures are only syndromic sets of symptoms. As Goodwin and Jamison [24] state, "mixed states can be broadly defined as the simultaneous presence of depressive and manic symptoms." Nevertheless, physicians cannot help associating them with an underlying, analogous physiopathologic alteration that they try to modify by treatment. Part of the problem lies in the term depression, which probably displaced melancholia because it was thought to convey the meaning of a state of mood rather than that of a disease entity. Clinicians and laypersons automatically relate such a state of depressed mood to lower activity of the nervous system, as Cullen did, and physicians today prescribe antidepressants to most patients who look and behave depressed, just as they prescribe antimanic medication for those who behave in an excited way. This concept of depression being caused by lower nervous activity is also borne out by the medical terms and popular expressions for despondent mood in most languages: Similar to the Latin depressio, the German Niedergedru ckt, the English downcast or down in the dumps, the French abattement, and the Spanish abatido, they all involve the idea of being low. Nosology and therapy of the so-called functional psychoses can be based only on their phenomenology, course, and outcome. The extensive use of effective psychotropic drugs, however, sheds new light and provides meaningful information on the underlying neurophysiologic conditions.

There is important clinical evidence, in fact, that excitatory brain processes may cause despondent mood, anxiety, and symptoms of inhibition. Stages II and III of mania, as described by Carlson and Goodwin, [13] with their dysphoric mood, panic, and hopelessness, are a perfect example of a condition that phenomenologically looks like a mixed state but neurophysiologically is a purely manic state, and useful treatments are exclusively antimanic.

The same applies to dysphoric mania, which is still considered a mixed state. [49] [55] [61] The useful treatments are antimanic ones, and typically, under their effect, euphoria replaces dysphoria before the patient becomes euthymic or depressed. A similar phenomenon may occur between excitement and psychomotor inhibition. In manic stupor, there is no inhibition of thought as Kraepelin believed. The patient does not speak, but when he or she recovers, the patient discloses that there were so many thoughts in his or her head racing so fast that the patient could not utter them. Also in the few cases of mania with poverty of ideas that the authors have seen, the patients reported that their heads were so full of thoughts that they could not express them or hold a conversation. As with mood in dysphoric mania, here too the inhibitory symptoms are solely due to an increase in the levels of excitement, and treatment is exclusively antimanic. Should they really be considered mixed states?

The case of agitated depression is different. As discussed subsequently, elements of clear excitement are bound together with authentic depressive elements. It is ironic that today agitated depression has lost

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its status as a mixed state, whereas manic stupor and dysphoric mania are still considered as such.

CLINICAL FORMS OF AGITATED DEPRESSION
In agitated depression, there is depressed, anxious mood; restlessness; inner agitation; and often racing or crowded thoughts. Three forms can be distinguished:

In psychotic agitated depression, alongside depressed mood, restlessness, and anxiety, the patient suffers delusions of guilt and persecution, hypochondriacal ideas, and strong suicidal impulses. The similarity of this syndrome with that of other psychotic depressions that do not present with motor agitation is notable. In the latter, the patient lies silently in bed. On questioning, the patient describes an intense inner agitation, often located in the chest, abdomen, or head. A young patient said he felt "blades ripping through his guts"--a similar image to that employed by Hippocrates. Other patients describe racing or crowded thoughts.
In nonpsychotic agitated depression, patients do not present delusions or hallucinations. The picture is dominated by anxiety and restlessness, with motor agitation similar to that described in the RDC criteria [65] . The patient may complain of crowded thoughts.
In excited anxious depression, the patient does not appear outwardly agitated, or the motor agitation is limited, but there is total lack of retardation. The patient speaks fluently and moves normally. The patient complains of intense inner agitation. The psychic pain of the patient is relentless, and the patient feels unable to perform normal tasks or enjoy anything. Frequently the patient complains of speeded thoughts (Table 1) .

TABLE 1 -- EXCITED ANXIOUS DEPRESSION Patient Displays Patient Complains of Partner Reports
Depressed mood Anxiety Continuous complaining
Psychic agitation Inner tension Occasional overt expression of irritability
Vivacious facial expression Muscular tension
Subjective feelings of irritability and unprovoked rage

Dramatic descriptions of suffering Crowded or racing thoughts Occasional sexual hyperactivity
Lack of retardation Initial or middle insomnia

Spells of weeping Suicidal ideas and impulses

Talkativeness

High diastolic blood pressure

Emotional lability

Impulsive suicidal attempts

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The last two forms are closely related. The main difference is that motor agitation prevails in the former, whereas racing thoughts and inner tension predominate in the latter.

The term excited anxious depression has been provisionally used to underline the mental excitement, psychic agitation, and anxious depressed mood of the patient. This term closely resembles the kraepelinian term excited depression[45] ; in Kraepelin's mixed state, the excitement is motor and coexists with inhibition of thought. In excited anxious depression, the excitement affects the patient's thoughts and produces inner agitation, whereas motor agitation is absent or limited. It is much closer to Lange's excitable depression, [46] as described earlier. The authors prefer the term excited to excitable because inner tension and racing thoughts are permanently present and not only when the patient is subjected to stimuli. If the patient is stimulated, however, agitation is exacerbated.

These patients fully meet the DSM-III criteria for major depression. Because of the absence of psychomotor agitation, they do not meet the RDC criteria for agitated depression and do not meet the criteria for a DSM-IV mixed affective episode because of the absence of a clear manic syndrome. Yet this form should be considered as a mixed state not only for the racing thoughts that are undoubtedly a sign of excitation, for the irritability, and for the emotional lability, but also for the course of this disorder and the reaction to antidepressant treatment. In a subsequent article arising from work on agitated depressions, the authors shall report systematic data on how antidepressant medications worsen agitation and insomnia and provoke or increase suicidal ideation and how in many cases the continued use of antidepressants could induce psychotic deterioration with delusions and violent suicidal attempts. Because of the lack of inhibition and because of the intense expression of their suffering, these patients are often diagnosed as presenting reactive or personality disorders. The syndrome may resemble hysteroid dysphoria[47] because of the vivacious expression of their suffering. These syndromes may occur spontaneously or appear de novo or become exacerbated during antidepressant treatment.

An interesting split is often observed between motor agitation and racing or crowded thoughts. Their relationship appears to be inversely proportional. Mental excitement is more frequent and more intense in patients who do not show marked motor agitation. There is a striking analogy with manic states, in which the presence of delusional ideas is inversely proportional to psychomotor excitement. This phenomenon may have played a decisive role in the success of political and religious fanatics who created a vast popular following. It can be assumed that if their delusional or semidelusional ideas had been accompanied by patent motor excitement, they would not have had the same charismatic influence on their audience.

Because all of the foregoing clinical forms of agitated depression have in common the full picture of a major depressive episode, whereas motor or psychic agitation and racing or crowded thoughts may be present in various combinations, and because they respond to treatments

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in the same way, the following diagnostic criteria are proposed to cover all forms of agitated depression:
Major depressive episode
At least two of the following symptoms:
Motor agitation
Psychic agitation or intense inner tension
Racing or crowded thoughts

Because the term agitation usually means motor agitation as in RDC and leaves out the cases of mental and psychic agitation, the term mixed depression is suggested for all the cases covered by the above-listed criteria.

It is also suggested that the old term melancholia be reused for the psychotic form of agitated depression. This name not only represents a great psychiatric tradition, but also fully conveys the tragic human experience of these patients and bears out a deeply significant fact--that the major psychiatric syndromes have remained unchanged over the course of thousands of years. If they are not disease entities, they surely are what Kraepelin would have called natural realities.

FLIGHT OF IDEAS, RACING AND CROWDED THOUGHTS
In all three forms of agitated depression delineated here, many patients complain of a disturbance of the train of thought or the pattern of thought that they call crowded thoughts or racing thoughts. Often, this is also called in the literature depression with flight of ideas. This disturbance is in many respects different from the flight of ideas observed in manic states:

Flight of ideas in manic patients is expressed verbally in an abundance of words or pressured or clearly logorrheic speech. When racing thoughts are present in depressed patients, speech is limited or at normal tempo.
In flight of ideas, the content of these ideas and somehow the pattern of thoughts are reflected in the content and pattern of the speech itself. In racing thoughts, there is not such a close relationship. On the contrary, the patient talks about the thoughts and reports on their course and their content and his or her own sensations. Racing thoughts are not expressed directly in the speech. The patient repeats monotonous laments, but the great energy involved in these depressive lamentations and in this speech denote the mixed depressive-manic nature of this symptom. In some cases, there is a certain degree of pressured speech.
The agitated melancholic patient complains of this course of thought as a torment, but the exalted (manic) patient never complains about his or her flight of ideas. This observation by Richarz [56] in 1858 in his paper on Melancholia Agitans is fully
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confirmed by the patients seen today. He introduced the term melancholia agitans instead of melancholia activa because it better suited the aimless restlessness of the patient. The term stayed in fashion for half a century until it was replaced by the term agitated depression at the beginning of the twentieth century.
Richarz [56] also observed that in mania thoughts tend to form strings of ideas (Reihenbildung von Vorstellungen) that link together by their content, alliteration, or assonance. In racing thoughts, the ideas come and go rapidly as if they were hunting each other or continuously overlapping without any link between them.

In Braden and Qualls' [12] work, the phenomenon is described by their patients with metaphors implying rotation: like a whirlpool, a hurricane, a centrifuge. A patient of the authors said, "I felt like the thoughts were circling around in my head and somehow I felt trapped by them." Another young woman said her thoughts were "like a raging river breaking through a dam and flooding my mind."

In other cases, the phenomenon could be called crowded thoughts; the patient complains that his or her head is full of thoughts of all kinds, not merely depressive ones and sad memories, but prevalently trivial thoughts of little significance for the patient. Not infrequently, patients report the presence of musical tunes that they keep hearing in their heads. The most important feature of these crowded or racing thoughts is that they afflict the patient not only through their meaning but also by the way they manifest themselves; there must be something unrelentingly painful and oppressive in their impact on the patient's mind.

A male patient said, "I felt attacked by them." Another male patient who tried unsuccessfully to shoot himself in the head said afterwards that he did it to stop his thoughts. This patient was of depressed mood and kept quiet. These kinds of thoughts are typically intense at night and often prevent the patient from falling asleep.

Depressive ruminations are different. They consist only of a few thoughts that carry the anxieties and fears of the patient, and they are constantly present or recur frequently. The patient complains of their content but not of their course. There are naturally cases of transition between crowded thoughts and ruminations.

Flight of ideas, racing thoughts, and crowded thoughts are clearly excitatory phenomena. Neuronal hyperactivity must underly them. This hyperactivity is dramatically confirmed by the effect of antidepressant medication, especially given without neuroleptics. The thoughts are further accelerated and intensified; the patient becomes exasperated to such a point that sometimes he or she wants to commit suicide. This worsening may be induced within the space of a few days or even hours. In many cases, the suicidal impulses induced by antidepressants seem to be linked to the acceleration of the thoughts and to the worsening of the agitation. Neuroleptics, on the contrary, are beneficial.

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RESTLESSNESS, INNER AGITATION, AND ANXIETY
I was awfully restless, I kept wringing my hands and tearing my hair. I couldn't sit still but had to keep pacing around all the time. I was not able to read or listen to music, I couldn't play the piano, I couldn't concentrate at all, I was unable to eat or sleep. I was irritable and constantly tired, I suffered from fears of going insane, of having contracted AIDS or syphilis and these thoughts did not leave me alone. I started thinking of oblivion, about suicide. I was so restless that I began to think of ending my life just to get some peace of mind.

This young woman called her agitated depression a horror.

Other patients exhibit much less psychomotor agitation, but they clearly suffer from inner agitation. They describe it as intense inner tension and use 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 found typically increased to 90 or 100 mm Hg. Psychomotor agitation and inner agitation are equally significant. Both are worsened by antidepressants and improved by neuroleptics. Psychic agitation is a subjective symptom, but it has objective manifestations observable by others, and the descriptions given by the patients are so characteristic as to make this symptom as reliable as any other aspect of affect and mood.

Closely related to this inner tension and agitation is a feeling of rage arising without external provocation and in most cases not directed against anything. The patient just complains about it. In other cases, there is irritability and, at times, verbal and rarely physical violence, usually within the family environment as noted by Lange. [46] In extreme cases, this rage is the cause of the violent character of suicide attempts, of which raptus melancholicus is the utmost example. The difference from manic aggressiveness is that in manic patients anger is provoked by some external cause and is directed outward.

The clinical picture comprises depressed mood, total anhedonia, exhaustion, and inability to perform simple tasks or take part in usual activities, and it is marked by intense anxiety and fears--fears about anything at all or psychotic fears, often hypochondriacal, especially the fear of losing one's mind. The devil figures frequently in these fears. One of the most common colloquial expressions for feeling low and fearful is "the blues," which originates from an old English expression alluding to an attack by "the blue devils."

Anxiety seems highly related not only to psychomotor agitation, but also to inner, psychic agitation. An interesting debate on anxiety in manic-depressive insanity, and particularly on melancholia agitata, took place at the beginning of the twentieth century, between Westphal and Koelpin [72] on one side and Specht [64] on the other. The former authors, following Wernicke, [71] who considered anxiety the basis of Angstpsychosen,

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maintained that anxiety overwhelms depressive inhibition and dominates the clinical picture, producing restlessness, agitation, and flight of ideas. Wernicke believed that the increased production of anxious thoughts could lead to flight of ideas, pressured speech, and agitation. A similar idea was advanced by Weitbrecht [70] in 1962. Mentzos [51] in his monograph on mixed states in 1967 proposes a distinction between anxious agitated depression and excited depression with flight of ideas.

Specht [64] sees agitation and flight of ideas as manic elements and considers melancholia agitata and agitated depression as mixed manic-depressive states. He makes the same assessment of melancholic delusions and proposes classifying every mixed state with depressive mood as melancholia. As far as anxiety is concerned, he thinks that the inhibition present in depressions of circular insanity dampens the anxiety, which is, on the contrary, freely manifested in cases without inhibition. Inhibition depresses all emotions and reactions, but anxiety is often completely absent in retarded depression. The anxiety found in typical depression (major depressive episode) is an emotional reaction to the painful experience of the depression itself. Human beings react with anxiety to stress factors of much lesser entity. This anxiety improves with antidepressant medication. Often, it is the first symptom to disappear. The anxiety observed in agitated depression seems to be of a different kind, inherent in the agitation itself. These two types of anxiety, assessed with limited semiologic tools, seem almost identical. The subjective suffering is similar, and they produce the same fears. Yet the anxiety present in agitated depression appears to be a form of excitation or arousal. By more careful examination of the patients, a substantial difference emerges between the anxiety of anxiety disorders, which consists of a feeling of apprehension, fearfulness, or impending doom,6 and the anxiety that often accompanies depressive episodes, which consists of fear of being worthless, fear of facing others, and fear of not getting better, in short, fear of something versus the inner tension of agitated depression. This latter anxiety seems similar to the two former types of anxiety but is substantially different. Patients of considerable introspective capacity describe this inner agitation as a great energy that strikes and possesses their minds and sometimes their bodies too, in a way that annihilates their capacity to think, feel, concentrate, or do anything. Racing thoughts have the same annihilating effect, probably because they are conveyed by this abnormal energy. It becomes impossible for the patient to cope with all of this because of the overwhelming sensation of total impotence. The total inactivity, the despair, the undirected and groundless rage, and the violent suicidal impulses, all the essential elements of classic melancholia and of the more mundane agitated depression of today, seem to be caused by that ominous, dark force. The long-standing Western tradition that has always associated the color black with melancholy and depression is probably linked to this force within the patient. This force is so violent that it cannot be anything but manic in nature. It improves rapidly under the effect of neuroleptic drugs, whereas it can worsen dramatically under the effect of antidepressants, especially if given without neuroleptics or discrete doses of benzodiazepines

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or anticonvulsant drugs. ECT is the most effective treatment. [36] A young woman called her agitated depression black mania, a term also used by Jamison. [32] Why this manic energy, rather than improving drive and mood, instead annihilates psychic life, is explained in the next section.

ROLE OF TEMPERAMENT
Many hypotheses have been advanced to explain the genesis of mixed states. Kraepelin's [44] idea of the unsynchronized transition between the two phases and the consequent hypothesis of the patient being "trapped in the switch process" may be accepted for transitional mixed states but not for the permanent ones. The most important mixed states either start as such or they become mixed under the effect of treatment. Himmelhoch et al [29] [30] advance the hypothesis of a double bipolar and unipolar heredity to explain the manic elements in a state of depression. McElroy [49] thinks that the agitation may be driven by hypomania.

Akiskal et al [1] [2] advance the groundbreaking hypothesis that mixed states arise from the intrusion of an affective episode into an opposite affective temperament or one with a high degree of chronic instability, such as the cyclothymic temperament. Thus, dysphoric mania results from the intrusion of a manic episode in a depressive temperament, and depressive mixed states arise from the intrusion of a depressive state into a hyperthymic (hypomanic) temperament.

The authors' view is similar to that of Akiskal. The premorbid temperament of depressed patients with motor or psychic agitation is marked by a high degree of excitability, emotional reactivity, and energetic drive. Many hyperthymic people and all cyclothymic and irritable people have such features, especially women, who make up the vast majority of agitated depressive patients. People with such temperament react intensely to stimuli in general and particularly to emotionally charged ones. They tend to have passionate love affairs, deeply felt disappointments, intense reactions to pleasure or frustration, deep artistic and religious experiences, and powerful fits of anger when irritated. The escalation of anger from initial irritation to outright rage typifies their reactive processes under stress or emotional stimuli. Their temperamental energy intensifies their emotions, and the emotions fire their energy. The authors' hypothesis is the following: When a sad or stressful event provokes a depressive reaction, or a seasonal or endogenous depression occurs in such a person, the psychic reaction is intense and exacerbates the depression itself. In turn, the emotional reaction heightens and unleashes this energy, which produces manic symptoms, such as restlessness and racing thoughts, while it also triggers anxiety and aggravates the depressive psychic pain. This tight interweaving of manic traits and depressive states of agitated depression makes it an authentic mixed state.

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SUMMARY
The extensive use of antidepressant drugs in the treatment of all forms of depression makes the question of the real nature of agitated depression a crucial issue because many patients have adverse outcomes, including increased agitation, increased insomnia, increased risk of suicide, and sometimes the onset of psychotic symptoms. Agitated depression is no longer considered a mixed state in the DSM system. After a review of the literature on melancholia agitata as a mixed state and on the introduction of the concept of mixed states, this article has examined the psychopathology of agitated depression. The main symptoms are depressive mood with marked anxiety, restlessness, and often delusions. In other cases, psychic agitation and racing or crowded thoughts prevail alongside anxiety and depressed mood. The mixed nature of these symptoms has been discussed and new diagnostic criteria proposed, including those syndromes without marked restlessness but with evident psychic agitation and racing or crowded thoughts. It is suggested that all the varieties of agitated depression be called mixed depression, with the following diagnostic criteria:

Major depressive episode
At least two of the following symptoms:
Motor agitation
Psychic agitation or intense inner tension
Racing or crowded thoughts

ACKNOWLEDGMENT
The authors acknowledge the valuable collaboration of Denis Greenan, Ulla Pouttu, Sirpa Hartman, and Lidia Spadafora Lombardi.
___________________________________
Address reprint requests to
Athanasios Koukopoulos, MD
Centro Lucio Bini
42, Via Crescenzio
00193 Rome, Italy
e-mail: [email protected]
___________________________________

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