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Depressive mixed states: A reappraisal of Koukopoulos׳criteria
Journal of Affective Disorders 176 (2015) 18–23
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Special review article
Depressive mixed states: A reappraisal of Koukopoulos'criteria Gianni L. Faedda a,b,c, Ciro Marangoni a,n, Daniela Reginaldi d a
Lucio Bini Mood Disorders Center, New York, NY, United States New York University Medical Center & Child Study Center, New York, NY, United States International Consortium for Bipolar Disorder Research, McLean Hospital, Belmont, MA, United States d Centro Lucio Bini, Rome, Italy b c
art ic l e i nf o
a b s t r a c t
Article history: Received 31 December 2014 Received in revised form 19 January 2015 Accepted 22 January 2015 Available online 4 February 2015
Background: Mixed states have been a fundamental part of Kraepelin's conceptualization of the manicdepressive illness. However, after Kraepelin, the study of mixed states was not of great interest, until the publication of the RDC criteria (1978) and then the DSM-III edition (1980), where criteria for mixed manic states were operationalized. The most notable victims of DSM nosology were depressive mixed states, in particular depression with flight of ideas and excited (agitated) depression. Methods: We briefly review the clinical work of Athanasios Koukopoulos on depressive mixed states (in particular agitated depression) pointing out the diagnostic and therapeutic contributions, especially in the lights of Koukopoulos' first description of depressive mixed syndrome in 1992. Results: The mixed depressive syndrome is not a transitory state but a state of long duration, which may last weeks or several months. The clinical picture is characterized by dysphoric mood, emotional lability, psychic and/or motor agitation, talkativeness, crowded and/or racing thoughts, rumination, initial or middle insomnia. Impulsive suicidal attempts may be frequent. The family observes incessant complaints, irritability, occasional verbal outbursts, occasional physical aggression, and occasional hypersexuality. Treatment with antipsychotics and ECT is very effective; antidepressants can worsen the clinical picture. Limitations: Selective but not systematic review of the literature on depressive mixed states. Relatively little research data is currently available for validation of the criteria proposed by Koukopoulos. Conclusions: Koukopoulos' proposal of mixed depression, besides its diagnostic implications, clearly identifying it as manifestations of bipolar disorder, allows for better clinical characterization of cases and improves treatment decisions. & 2015 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Mixed states Mixed mania Agitated depression Mixed depression
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Diagnostic contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Therapeutic contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
n Correspondence to: via Ponte Assa 80, 44123 Ferrara, Italy. Tel./fax: þ 39 0532 427722. E-mail address: [email protected] (C. Marangoni).
http://dx.doi.org/10.1016/j.jad.2015.01.053 0165-0327/& 2015 Elsevier B.V. All rights reserved.
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1. Introduction Since the shift from Kraepelin's classification of mood disorders based on course and recurrence rate to that of Leonhard based on polarity (Goodwin and Jamison, 2007), the study of mixed states, either as transitional states or recurrent episodes of the manicdepressive illness, was not of great interest, with a few notable exceptions (Lange, 1928; Campbell, 1953; Winokur et al., 1969). Schneider (1962) stated: “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”. Mixed states' nosological position and their clinical importance was not recognized until the publication of the Research Diagnostic Criteria (Spitzer et al., 1978) and then the Diagnostic and Statistical Manual for Mental Disorders (DSM) III edition criteria (APA, 1980); according to DSM criteria, a mixed state was the combination of a full manic episode with a major depressive episode (MDE) and belonged only to bipolar I disorder. Therefore, all mixed states were mixed manic episodes. The most notable victims of the adoption of this neo-Leonhardian nosological approach were depressive mixed states, especially Kraepelin's depression with flight of ideas, and excited (agitated) depression (Koukopoulos and Koukopoulos, 1999); in fact in the DSM-III, the category of major depressive disorder (MDD) was expanded to include most depressive states, including melancholic depression (with psychomotor retardation and anhedonia) and agitated depression (an RDC subtype). The nosological outcome was the disappearance of all depressive mixed states from DSM. This clinical gap has been reduced by the DSM-5, with the introduction of the mixed feature specifier applicable to manic, hypomanic and major depressive episodes, both in bipolar I/II disorder and in MDD (Tables 1 and 2).
2. Methods We briefly reviewed the psychiatric literature on bipolar mixed states, available in English language, published before 1992. In particular we focused on an article written by Koukopoulos in 1992 in which he described the psychopathological features, the clinical course and the treatment response of mixed depressive syndrome. That article, written in French, was never translated in English; excerpts of the article are included to underscore its importance for the study of mixed states.
3. Results In the late 70s and in the 80s, the work of several American and European psychiatrists contributed to the renewed interest in mixed features (Mentzos, 1967; Kotin and Goodwin, 1972; Himmelhoch et al., 1976; Akiskal and Puzantian, 1979; Kukopulos et al., 1983; Keller et al., 1986; Berner et al., 1987; Secunda et al., 1987). Following the publication of a review article on bipolar mixed states by McElroy et al. (1992) there has been increased clinical and research interest in bipolar mixed states, with more than 2000 articles on bipolar mixed states have been published since than. This surge in interest in mixed states stems from a deeper understanding of their relative contribution to morbidity and mortality in patients with bipolar disorders. While most American psychiatrists were focused on mixed features of mania (often referred to as irritable or dysphoric mania), there was less interest in depressive mixed states, as there were no criteria to diagnose them. The heterogeneity of depressive syndromes, blurred by the DSM's classification, was evident to clinicians, with heterogeneous outcomes to antidepressant treatment. As pointed out by several authors (Wehr and Goodwin, 1979; Kukopulos et al., 1980; Tondo et al., 1981; Akiskal and Mallya, 1987), a significant minority of depressive
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episodes cycles rapidly with exposure to antidepressants: some of these ‘refractory depression’ worsen with antidepressants, improve with discontinuation of antidepressants and treatment with sedatives. Some reports on the presence and clinical importance of hypomanic symptoms (like racing thoughts) during depression were appearing in the 80s (Braden and Qualls, 1979; Akiskal and Mallya, 1987). Among the mixed states, the concept of agitated depression combined syndromal features of depression with severe psychomotor agitation (Koukopoulos and Koukopoulos, 1999). This concept had its roots in Franz Richarz's Melancholia Agitans and overlaps well with Weygandt's agitated depression, as the syndrome of mania or hypomania is not present (Koukopoulos and Koukopoulos, 1999). In 1992, Koukopoulos and colleagues of the Centro Lucio Bini in Rome published an article describing a group of mood disordered patients affected by a mixed depressive syndrome, characterized by the lack of psychomotor retardation (agitation), labile/irritable mood and psychic agitation or inner tension (Koukopoulos et al., 1992). That article, written in French, was never translated in English; excerpts of the article are included to underscore its importance for the study of mixed states. (…) The main characteristics of the patient's behavior are: a) he suffers a lot; b) he is not retarded. He speaks freely, his facial expression and gestures are lively and he expresses his suffering in a dramatic way. This feature of intense emotivity and marked expression of feelings with weeping fits in women often leads to diagnostic errors. The patient is regarded as hysterical or as an emotional person suffering from a depressive reaction (…) Mood oscillates from melancholic to dysphoric (Berner et al., 1987) and often reaches despair (…) The patient displays: dysphoric mood, absence of retardation, dramatic expressions of suffering, bouts of weeping, vivacious facial expression, talkativeness, psychic and/or motor agitation, emotional lability, impulsive suicidal attempts, high diastolic blood pressure (…) (…) The most specific symptoms of this affective state are subjective symptoms and are described by the patient himself. He complains of inner tension, which is different from anxiety, although it is not always easy to distinguish one from the other by the patient's description (…) The patient complains of: anxiety, inner tension, irritability, anger, despair, suicidal impulses (like raptus), crowded and/or racing thoughts, rumination, initial or middle insomnia. (…) In certain cases the patient has a sensation of severe tension inside his head, “as if it was about to explode.” The feelings of irritability and anger are, more clearly, of an excitatory nature. In manic patients irritability and anger ensue and lead to aggressive behavior. In our patients, they are spontaneous feelings that have nothing to do with their environment and, usually, they do not lead to aggressive acts. Sometimes the patient may have a verbal, or very rarely physical, outburst, solely in his family environment (Lange, 1928). The patient commonly suffers from sexual inhibition but occasionally has strong sexual excitation. These symptoms, as well as the bouts of aggressiveness, are never reported by the patient but only by someone around him. (…) The family observes: incessant complaints, irritability, occasional verbal outbursts, occasional physical aggression, occasional hypersexuality (…) (…) Suicide attempts are impulsive and often violent and are repeated. The ideas of suicide, too, are marked by sudden impulses and are not the result of pessimistic thoughts or feelings. An important reaction to antidepressants is the appearance or the accentuation of these suicidal impulses (…) (…) This syndrome is not rare. In order to evaluate its frequency compared to other depressions, we examined all the patients with mood disorders we treated, both as in-patients and as outpatients,
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Table 1 Evolution of the diagnostic criteria of mixed states in the DSM editions. DSM edition
Criteria for mixed states
I (1952) II (1968)
No specific criteria, included among manic depressive reaction, other. No specific criteria, included among ‘manic depressive reaction, other’. ‘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’. III (1980) Introduces the term bipolar as opposed to unipolar; mixed states are recognized as a subtype of bipolar disorder (Bipolar Disorder, Mixed). A. Current (or most recent) episode involves the full symptomatic picture of both manic and major depressive episodes, intermixed or rapidly alternating every few days. B. Depressive symptoms are prominent and last at least a full day. III-R (1987) Mixed states are recognized as a subtype of bipolar disorder (bipolar disorder, mixed). A. Current (or most recent) episode involves the full symptomatic picture of both manic and major depressive episodes (except for the duration requirement of two weeks for depressive symptoms), intermixed or rapidly alternating every few days. B. Prominent depressive symptoms lasting at least a full day. IV (1994) Introduces mixed state as a specific episode of illness belonging to Bipolar I Disorder (bipolar I disorder, mixed episode). A. The criteria are met both for a manic episode and for a major depressive episode (except for duration) nearly every day during at least a 1-week period. B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar I disorder. IV-TR Same criteria as DSM-IV. (2000) 5 (2013) The mixed features specifier can apply to the current manic, hypomanic, or depressive episode in bipolar I or bipolar II disorder or major depressive disorder: Manic or hypomanic episode, with mixed features: A. Full criteria are met for a manic episode or hypomanic episode, and at least three of the following symptoms are present during the majority of days of the current or most recent episode of mania or hypomania: - Prominent dysphoria or depressed mood as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). - Diminished interest or pleasure in all, or almost all, activities (as indicated by either subjective account or observation made by others). - Psychomotor retardation nearly every day (observable by others; not merely subjective feelings of being slowed down). - Fatigue or loss of energy. - Feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick). - Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. B. Mixed symptoms are observable by others and represent a change from the person's usual behavior. C. For individuals whose symptoms meet full episode criteria for both mania and depression simultaneously, the diagnosis should be manic episode, with mixed features, due to the marked impairment and clinical severity of full mania. D. The mixed symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, other treatment). Depressive episode, with mixed features: A. Full criteria are met for a major depressive episode, and at least three of the following manic/hypomanic symptoms are present during the majority of days of the current or most recent episode of depression: Elevated, expansive mood. Inflated self-esteem or grandiosity. More talkative than usual or pressure to keep talking. Flight of ideas or subjective experience that thoughts are racing. Increase in energy or goal-directed activity (either socially, at work or school, or sexually). 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). Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted with insomnia). B. Mixed symptoms are observable by others and represent a change from the person's usual behavior. C. For individuals whose symptoms meet full episode criteria for both mania and depression simultaneously, the diagnosis should be manic episode, with mixed features. D. The mixed symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment). Note: Mixed features associated with a major depressive episode have been found to be a significant risk factor for the development of bipolar I or bipolar II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring of response to treatment.
at the Centro Lucio Bini in Rome, between April 1 and October 1, 1990. Of the 361 patients, 181 suffered from major depression according to the DSM-III-R criteria; of the latter, 46 suffered from the mixed state described above (…) (…) ECT is very effective. Improvement is swift. Usually, after the first ECT treatment one sees the suffering abate. The patients have a very low convulsive threshold, sometimes even less than 10 J, and the convulsions are very long: from 60 to 120 s. What is more remarkable is that the same patients when they relapse into a simple depression respond less well to ECT and a higher number of sessions is required. The convulsive threshold also increases. These data, as well as the clinical picture, lead us to think that this mixed
state is not the combination of depressive and manic symptoms but rather a different affective state. In fact, it is not a transitory state but a state of long duration, which may last weeks or several months (…)
4. Discussion Koukopoulos' proposal of mixed depression, besides its diagnostic implications, clearly identifying it as manifestations of bipolar disorder, allows for better clinical characterization of cases and improve treatment decisions. Koukopoulos used premorbid temperament, course of illness, family history, worsening with
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Table 2 Evolution of the manic-depressive illness from Kraepelin to DSM-5. Kraepelin
DSM-I
DSM-II
DSM-III
DSM-III R
DSM-IV
DSM-IV TR
DSM-5
Manic depressive reaction, manic type Not recognized Not recognized
Manicdepressive illness, manic type1 Not recognized Not recognized
Manic episode
Manic episode
Manic episode
Manic episode
Manic episode
Atypical bipolar disorder Manic episode, with mood congruent/ incongruent psychotic features
Hypomanic episode
Hypomanic episode
Hypomanic episode
Hypomanic episode
Manic episode, with mood congruent/ incongruent psychotic features
Manic episode, with mood congruent/ incongruent psychotic features
Manic episode, with mood congruent/ incongruent psychotic features
Delirious mania (acute confusion) Depressive states
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Manic episode, with mood congruent/ incongruent psychotic features Not recognized
Melancholia simplex (depressed mood, psychomotor inhibition)
Manic depressive reaction, depressive type Manic depressive reaction, depressive type Not recognized
Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Not recognized
Major depressive episode3, with melancholia
Major depressive episode3, melancholic type
Major depressive Major depressive Major depressive episode3, with episode3, with episode3, with melancholic features melancholic features melancholic features
Not recognized
Not recognized
Major depressive episode3, with catatonic features
Major depressive episode3, with catatonic features
Major depressive episode3, with catatonia
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with mood-congruent psychotic features
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with mood-incongruent psychotic features
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with mood-incongruent psychotic features
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Manic states Mania
Hypomania Delusional mania (elaborated delusions and hallucinations)
Melancholic stupor (depressed mood, marked psychomotor inhibition) Melancholia gravis (mood congruent delusions)
Paranoid melancholia (hallucinations and persecutory delusions)
Not recognized
Not Fantastic melancholia (marked hallucinations recognized and interpretative delusions) Delirious melancholia (acute confusion) Mixed states
Not recognized
Depressive mania (depressed mood, flight of ideas, excitement, anxiety) Excited depression (depressed mood, poverty of thought, great restlessness)
Not recognized
Other major Bipolar disorder, mixed affective disorder
Bipolar disorder, mixed
Mixed episode
Mixed episode
Major depressive episode3, with mixed features
Manic depressive reaction, depressed type Not recognized
Manicdepressive illness, depressive type2 Other major affective disorder
Not recognized
Not recognized
Not recognized
Not recognized
Major depressive episode3, with mixed features
Manic episode with psychotic features, mood-incongruent
Manic episode with psychotic features, mood-incongruent
Manic episode, with catatonic features
Manic episode, with catatonic features
Manic episode, with catatonia
Manic depressive reaction, other Not recognized
Other major Manic episode with psychotic features, affective mood-incongruent disorder
Manic episode with psychotic features, mood-incongruent
Manic episode, with catatonic features
Manic episode, with catatonic features
Manic episode, with catatonia
Other major Not recognized affective disorder
Not recognized
Not recognized
Not recognized
Major depressive episode3, with mixed features
Manic depressive reaction, other
Other major Manic episode with psychotic features, affective mood-incongruent disorder
Manic episode with psychotic features, mood-incongruent
Manic episode, with catatonic features
Manic episode, with catatonic features
Manic episode, with catatonia
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Mania with poverty of thought (euphoric mood, poverty of thought, less excitement) Manic stupor (euphoric mood, marked psychomotor inhibition) Depression with flight of ideas (depressed mood, flight of ideas, psychomotor inhibition) Inhibited mania (euphoric mood, flight of ideas, psychomotor inhibition) Fundamental states Manic temperament
Not recognized
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Table 2 (continued ) Kraepelin
DSM-I
DSM-II
DSM-III
DSM-III R
DSM-IV
DSM-IV TR
DSM-5
Not recognized Depressive temperament Not recognized
Not recognized Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Dysthymic disorder
Dysthymic disorder
Dysthymic disorder
Dysthymic disorder
Cyclothymic temperament
Not recognized
Irritable temperament
Not recognized
Persistent depressive disorder (dysthymia) Cyclothymic disorder Cyclothymic disorder Cyclothymic disorder Cyclothymic disorder Cyclothymic disorder
Notes: 1) this disorder consists exclusively of manic episodes; 2) this disorder consists exclusively of depressive episodes; 3) major depressive episode applies both to bipolar disorder and major depressive disorder; from DSM-III to DSM-IV TR, bipolar disorder and major depressive disorder have been put together in the mood disorders category; in the DSM-5 they are two separate categories (bipolar and related disorders; depressive disorders).
antidepressant/stimulants treatment and improvement with sedatives and ECT as independent validators of both, the bipolar nature of these episodes and their independent nosological status. He suggested that these mixed symptoms during MDE were often misdiagnosed as agitated depression, and should be regarded as a risk factor for suicide and rapid cycling course of illness. Koukopoulos' conceptualization of mixed states is well within his later proposal of the primacy of mania, here presenting as ‘hypomanic equivalents’ (racing/crowded thoughts, heightened anxiety, aggressive impulses, psychomotor agitation and sleep disturbances) during a depressive episode as important factors in the clinical evolution and treatment response (Koukopoulos and Ghaemi, 2009). The excitatory nature of these symptoms is confirmed by its response to antimanic and or sedative agents; such treatments would instead worsen the clinical picture if its nature was pure depressive. Additionally these excitatory symptoms occurred only after (or increased following) treatment with antidepressants or use of stimulants such as caffeine, amphetamines or cocaine. Additionally, the exclusion of overlapping criteria such as irritability, agitation and distractibility, effectively makes much more difficult to meet diagnostic criteria. In fact, failing to exclude the overlapping symptoms would result in approximately half of the depressive states being reclassified as mixed (Angst et al., 2011). A limitation of this article is the selective but not systematic review of the literature on depressive mixed states. Relatively little research data is currently available for validation of the criteria proposed by Koukopoulos. In the DSM-5, the status of mixed depressive syndromes is more uncertain than before (Koukopoulos et al., 2013). This is likely to further complicate the proper diagnosis and treatment of depressive mixed states ignoring the rich literature clearly indicating the bipolar nature of such common clinical presentations. In summary, Koukopoulos's diagnostic and therapeutic contributions on the psychopathology and treatment of bipolar mixed depression can be summarized as follows:
4.1. Diagnostic contributions 1) Mixed states extend well beyond the DSM criteria currently used in research and practice; besides mania with dysphoric/mixed features, many patients presenting with MDD can experience hypomanic symptoms as in mixed depression. 2) Hypomanic symptoms occurring during MDE are common, representing ¼ outpatients with MDE (33% in women). This finding has been recently replicated (Sani et al., 2014a, 2014b). 3) The clinical presentation of mixed states is similar to certain form of agitated depression. 4) Hypomanic symptoms during MDE increase the risk of suicidal ideation and behaviors. 5) Premorbid temperamental features, especially hyperthymic and cyclothymic temperaments, are often responsible for such mixed depressive presentations.
6) Family history for recurrent depression and bipolar disorders might distinguish such presentations from unipolar depressives. 4.2. Therapeutic contributions 1) The presence of such hypomanic features might explain the worsening of symptoms during antidepressant treatment (except for ECT) even the suicidal ideation/gestures. 2) Discontinuation of antidepressant treatments (other than ECT) often improved the clinical presentation, with decreased agitation, tension or racing thoughts, better sleep and decreased suicidal ideation. 3) The beneficial response to sedatives including benzodiazepins and antipsychotis appears to confirm the excitatory nature of such mixed presentations during bipolar depressive episodes; a recent study found an atypical antipsychotic to be specifically effective for mixed depressive syndromes (Patkar et al., 2012). Role of funding source Nothing declared.
Conflict of interest No conflict declared.
Aknowledgments Nothing to disclose.
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Koukopoulos, A., Sani, G., Ghaemi, N.S., 2013. Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV). Br. J. Psychiatry 203, 3–5. Koukopoulos, A., Faedda, G., Proietti, R., D’Amico, S., De Pisa, E., Simonetto, C., 1992. Un syndrome dépressif mixte. L’Encéphale 18, 19–21. Koukopoulos, A., Koukopoulos, A., 1999. Agitated depression as a mixed state and the problem of melancholia. Psychiatr. Clin. N. Am. 22, 547–564. Koukopoulos, A., Ghaemi, S.N., 2009. The primacy of mania: a reconsideration of mood disorders. Eur. Psychiatry 24, 125–134. Kukopulos, A., Reginaldi, D., Laddomada, P., Floris, G., Serra, G., Tondo, L., 1980. Course of the manic-depressive cycle and changes caused by treatment. Pharmakopsychiatr. Neuro-Psychopharmakol. 13, 156–167. Kukopulos, A., Caliari, B., Tundo, A., Minnai, G., Floris, G., Reginaldi, D., Tondo, L., 1983. Rapid cyclers, temperament, and antidepressants. Compr. Psychiatry 24, 249–258. Lange, J, 1928. Die endogenen und reaktiven Gemuetserkrankungen und die manische-depressive KonstitutionIn: Bumke, O. (Ed.), Handbuch der Geisteskrankheiten. Bd. 6, Spezieller Teil. Springer, Berlin, p. 2. McElroy, S.L., Keck Jr, P.E., Pope Jr, H.G., Hudson, J.I., Faedda, G.L., Swann, A.C., 1992. Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am. J. Psychiary 149, 1633–1644. Mentzos, S., 1967. Mischzustaende und mischbildhafte phasische psychosen. Enke, Stuttgart.
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Patkar, A., Gilmer, W., Pae, C.U., Vöhringer, P.A., Ziffra, M., Pirok, E., Mulligan, M., Filkowski, M.M., Whitham, E.A., Holtzman, N.S., Thommi, S.B., Logvinenko, T., Loebel, A., Masand, P., Ghaemi, S.N., 2012. A 6 weeks randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS One 7 (4), e34757. Sani, G., Napoletano, F., Vö hringer, P.A., Sullivan, M., Simonetti, A., Koukopoulos, A., Danese, E., Girardi, P., Ghaemi, N.S., 2014a. Mixed depression: clinical features and predictors of its onset associated with antidepressant use. Psychother. Psychosom. 83, 213–221. Sani, G., Vö hringer, P.A., Napoletano, F., Holtzman, N.S., Dalley, S., Girardi, P., Ghaemi, N.S., Koukopoulos, A., 2014b. Koukopoulos' diagnostic criteria for mixed depression: a validation study. J. Affect. Disord. 164, 14–18. Schneider, K., 1962. Klinische Psychopathologie. Thieme Verlag, Stuttgart. Secunda, S.K., Swann, A., Katz, M.M., Koslow, S.H., Croughan, J., Chang, S., 1987. Diagnosis and treatment of mixed mania. Am. J. Psychiatry 144, 96–98. Spitzer, R.L., Endicott, J., Robins, E., 1978. Research Diagnostic Criteria (RDC). New York State Psychiatric Institute, New York. Tondo, L., Laddomada, P., Serra, G., Minnai, G., Kukopulos, A., 1981. Rapid cyclers and antidepressants. Int. Pharmacopsychiatry 16, 119–123. Wehr, T.A., Goodwin, F.K., 1979. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch. Gen. Psychiatry 36, 555–559. Winokur, G., Clayton, P.J., Reich, T., 1969. Manic Depressive IllnessCV Mosby, St. Louis.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Special review article
Depressive mixed states: A reappraisal of Koukopoulos'criteria Gianni L. Faedda a,b,c, Ciro Marangoni a,n, Daniela Reginaldi d a
Lucio Bini Mood Disorders Center, New York, NY, United States New York University Medical Center & Child Study Center, New York, NY, United States International Consortium for Bipolar Disorder Research, McLean Hospital, Belmont, MA, United States d Centro Lucio Bini, Rome, Italy b c
art ic l e i nf o
a b s t r a c t
Article history: Received 31 December 2014 Received in revised form 19 January 2015 Accepted 22 January 2015 Available online 4 February 2015
Background: Mixed states have been a fundamental part of Kraepelin's conceptualization of the manicdepressive illness. However, after Kraepelin, the study of mixed states was not of great interest, until the publication of the RDC criteria (1978) and then the DSM-III edition (1980), where criteria for mixed manic states were operationalized. The most notable victims of DSM nosology were depressive mixed states, in particular depression with flight of ideas and excited (agitated) depression. Methods: We briefly review the clinical work of Athanasios Koukopoulos on depressive mixed states (in particular agitated depression) pointing out the diagnostic and therapeutic contributions, especially in the lights of Koukopoulos' first description of depressive mixed syndrome in 1992. Results: The mixed depressive syndrome is not a transitory state but a state of long duration, which may last weeks or several months. The clinical picture is characterized by dysphoric mood, emotional lability, psychic and/or motor agitation, talkativeness, crowded and/or racing thoughts, rumination, initial or middle insomnia. Impulsive suicidal attempts may be frequent. The family observes incessant complaints, irritability, occasional verbal outbursts, occasional physical aggression, and occasional hypersexuality. Treatment with antipsychotics and ECT is very effective; antidepressants can worsen the clinical picture. Limitations: Selective but not systematic review of the literature on depressive mixed states. Relatively little research data is currently available for validation of the criteria proposed by Koukopoulos. Conclusions: Koukopoulos' proposal of mixed depression, besides its diagnostic implications, clearly identifying it as manifestations of bipolar disorder, allows for better clinical characterization of cases and improves treatment decisions. & 2015 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Mixed states Mixed mania Agitated depression Mixed depression
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Diagnostic contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Therapeutic contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
n Correspondence to: via Ponte Assa 80, 44123 Ferrara, Italy. Tel./fax: þ 39 0532 427722. E-mail address: [email protected] (C. Marangoni).
http://dx.doi.org/10.1016/j.jad.2015.01.053 0165-0327/& 2015 Elsevier B.V. All rights reserved.
18 19 19 20 22 22 22 22 22 22
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1. Introduction Since the shift from Kraepelin's classification of mood disorders based on course and recurrence rate to that of Leonhard based on polarity (Goodwin and Jamison, 2007), the study of mixed states, either as transitional states or recurrent episodes of the manicdepressive illness, was not of great interest, with a few notable exceptions (Lange, 1928; Campbell, 1953; Winokur et al., 1969). Schneider (1962) stated: “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”. Mixed states' nosological position and their clinical importance was not recognized until the publication of the Research Diagnostic Criteria (Spitzer et al., 1978) and then the Diagnostic and Statistical Manual for Mental Disorders (DSM) III edition criteria (APA, 1980); according to DSM criteria, a mixed state was the combination of a full manic episode with a major depressive episode (MDE) and belonged only to bipolar I disorder. Therefore, all mixed states were mixed manic episodes. The most notable victims of the adoption of this neo-Leonhardian nosological approach were depressive mixed states, especially Kraepelin's depression with flight of ideas, and excited (agitated) depression (Koukopoulos and Koukopoulos, 1999); in fact in the DSM-III, the category of major depressive disorder (MDD) was expanded to include most depressive states, including melancholic depression (with psychomotor retardation and anhedonia) and agitated depression (an RDC subtype). The nosological outcome was the disappearance of all depressive mixed states from DSM. This clinical gap has been reduced by the DSM-5, with the introduction of the mixed feature specifier applicable to manic, hypomanic and major depressive episodes, both in bipolar I/II disorder and in MDD (Tables 1 and 2).
2. Methods We briefly reviewed the psychiatric literature on bipolar mixed states, available in English language, published before 1992. In particular we focused on an article written by Koukopoulos in 1992 in which he described the psychopathological features, the clinical course and the treatment response of mixed depressive syndrome. That article, written in French, was never translated in English; excerpts of the article are included to underscore its importance for the study of mixed states.
3. Results In the late 70s and in the 80s, the work of several American and European psychiatrists contributed to the renewed interest in mixed features (Mentzos, 1967; Kotin and Goodwin, 1972; Himmelhoch et al., 1976; Akiskal and Puzantian, 1979; Kukopulos et al., 1983; Keller et al., 1986; Berner et al., 1987; Secunda et al., 1987). Following the publication of a review article on bipolar mixed states by McElroy et al. (1992) there has been increased clinical and research interest in bipolar mixed states, with more than 2000 articles on bipolar mixed states have been published since than. This surge in interest in mixed states stems from a deeper understanding of their relative contribution to morbidity and mortality in patients with bipolar disorders. While most American psychiatrists were focused on mixed features of mania (often referred to as irritable or dysphoric mania), there was less interest in depressive mixed states, as there were no criteria to diagnose them. The heterogeneity of depressive syndromes, blurred by the DSM's classification, was evident to clinicians, with heterogeneous outcomes to antidepressant treatment. As pointed out by several authors (Wehr and Goodwin, 1979; Kukopulos et al., 1980; Tondo et al., 1981; Akiskal and Mallya, 1987), a significant minority of depressive
19
episodes cycles rapidly with exposure to antidepressants: some of these ‘refractory depression’ worsen with antidepressants, improve with discontinuation of antidepressants and treatment with sedatives. Some reports on the presence and clinical importance of hypomanic symptoms (like racing thoughts) during depression were appearing in the 80s (Braden and Qualls, 1979; Akiskal and Mallya, 1987). Among the mixed states, the concept of agitated depression combined syndromal features of depression with severe psychomotor agitation (Koukopoulos and Koukopoulos, 1999). This concept had its roots in Franz Richarz's Melancholia Agitans and overlaps well with Weygandt's agitated depression, as the syndrome of mania or hypomania is not present (Koukopoulos and Koukopoulos, 1999). In 1992, Koukopoulos and colleagues of the Centro Lucio Bini in Rome published an article describing a group of mood disordered patients affected by a mixed depressive syndrome, characterized by the lack of psychomotor retardation (agitation), labile/irritable mood and psychic agitation or inner tension (Koukopoulos et al., 1992). That article, written in French, was never translated in English; excerpts of the article are included to underscore its importance for the study of mixed states. (…) The main characteristics of the patient's behavior are: a) he suffers a lot; b) he is not retarded. He speaks freely, his facial expression and gestures are lively and he expresses his suffering in a dramatic way. This feature of intense emotivity and marked expression of feelings with weeping fits in women often leads to diagnostic errors. The patient is regarded as hysterical or as an emotional person suffering from a depressive reaction (…) Mood oscillates from melancholic to dysphoric (Berner et al., 1987) and often reaches despair (…) The patient displays: dysphoric mood, absence of retardation, dramatic expressions of suffering, bouts of weeping, vivacious facial expression, talkativeness, psychic and/or motor agitation, emotional lability, impulsive suicidal attempts, high diastolic blood pressure (…) (…) The most specific symptoms of this affective state are subjective symptoms and are described by the patient himself. He complains of inner tension, which is different from anxiety, although it is not always easy to distinguish one from the other by the patient's description (…) The patient complains of: anxiety, inner tension, irritability, anger, despair, suicidal impulses (like raptus), crowded and/or racing thoughts, rumination, initial or middle insomnia. (…) In certain cases the patient has a sensation of severe tension inside his head, “as if it was about to explode.” The feelings of irritability and anger are, more clearly, of an excitatory nature. In manic patients irritability and anger ensue and lead to aggressive behavior. In our patients, they are spontaneous feelings that have nothing to do with their environment and, usually, they do not lead to aggressive acts. Sometimes the patient may have a verbal, or very rarely physical, outburst, solely in his family environment (Lange, 1928). The patient commonly suffers from sexual inhibition but occasionally has strong sexual excitation. These symptoms, as well as the bouts of aggressiveness, are never reported by the patient but only by someone around him. (…) The family observes: incessant complaints, irritability, occasional verbal outbursts, occasional physical aggression, occasional hypersexuality (…) (…) Suicide attempts are impulsive and often violent and are repeated. The ideas of suicide, too, are marked by sudden impulses and are not the result of pessimistic thoughts or feelings. An important reaction to antidepressants is the appearance or the accentuation of these suicidal impulses (…) (…) This syndrome is not rare. In order to evaluate its frequency compared to other depressions, we examined all the patients with mood disorders we treated, both as in-patients and as outpatients,
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Table 1 Evolution of the diagnostic criteria of mixed states in the DSM editions. DSM edition
Criteria for mixed states
I (1952) II (1968)
No specific criteria, included among manic depressive reaction, other. No specific criteria, included among ‘manic depressive reaction, other’. ‘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’. III (1980) Introduces the term bipolar as opposed to unipolar; mixed states are recognized as a subtype of bipolar disorder (Bipolar Disorder, Mixed). A. Current (or most recent) episode involves the full symptomatic picture of both manic and major depressive episodes, intermixed or rapidly alternating every few days. B. Depressive symptoms are prominent and last at least a full day. III-R (1987) Mixed states are recognized as a subtype of bipolar disorder (bipolar disorder, mixed). A. Current (or most recent) episode involves the full symptomatic picture of both manic and major depressive episodes (except for the duration requirement of two weeks for depressive symptoms), intermixed or rapidly alternating every few days. B. Prominent depressive symptoms lasting at least a full day. IV (1994) Introduces mixed state as a specific episode of illness belonging to Bipolar I Disorder (bipolar I disorder, mixed episode). A. The criteria are met both for a manic episode and for a major depressive episode (except for duration) nearly every day during at least a 1-week period. B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar I disorder. IV-TR Same criteria as DSM-IV. (2000) 5 (2013) The mixed features specifier can apply to the current manic, hypomanic, or depressive episode in bipolar I or bipolar II disorder or major depressive disorder: Manic or hypomanic episode, with mixed features: A. Full criteria are met for a manic episode or hypomanic episode, and at least three of the following symptoms are present during the majority of days of the current or most recent episode of mania or hypomania: - Prominent dysphoria or depressed mood as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). - Diminished interest or pleasure in all, or almost all, activities (as indicated by either subjective account or observation made by others). - Psychomotor retardation nearly every day (observable by others; not merely subjective feelings of being slowed down). - Fatigue or loss of energy. - Feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick). - Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. B. Mixed symptoms are observable by others and represent a change from the person's usual behavior. C. For individuals whose symptoms meet full episode criteria for both mania and depression simultaneously, the diagnosis should be manic episode, with mixed features, due to the marked impairment and clinical severity of full mania. D. The mixed symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, other treatment). Depressive episode, with mixed features: A. Full criteria are met for a major depressive episode, and at least three of the following manic/hypomanic symptoms are present during the majority of days of the current or most recent episode of depression: Elevated, expansive mood. Inflated self-esteem or grandiosity. More talkative than usual or pressure to keep talking. Flight of ideas or subjective experience that thoughts are racing. Increase in energy or goal-directed activity (either socially, at work or school, or sexually). 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). Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted with insomnia). B. Mixed symptoms are observable by others and represent a change from the person's usual behavior. C. For individuals whose symptoms meet full episode criteria for both mania and depression simultaneously, the diagnosis should be manic episode, with mixed features. D. The mixed symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment). Note: Mixed features associated with a major depressive episode have been found to be a significant risk factor for the development of bipolar I or bipolar II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring of response to treatment.
at the Centro Lucio Bini in Rome, between April 1 and October 1, 1990. Of the 361 patients, 181 suffered from major depression according to the DSM-III-R criteria; of the latter, 46 suffered from the mixed state described above (…) (…) ECT is very effective. Improvement is swift. Usually, after the first ECT treatment one sees the suffering abate. The patients have a very low convulsive threshold, sometimes even less than 10 J, and the convulsions are very long: from 60 to 120 s. What is more remarkable is that the same patients when they relapse into a simple depression respond less well to ECT and a higher number of sessions is required. The convulsive threshold also increases. These data, as well as the clinical picture, lead us to think that this mixed
state is not the combination of depressive and manic symptoms but rather a different affective state. In fact, it is not a transitory state but a state of long duration, which may last weeks or several months (…)
4. Discussion Koukopoulos' proposal of mixed depression, besides its diagnostic implications, clearly identifying it as manifestations of bipolar disorder, allows for better clinical characterization of cases and improve treatment decisions. Koukopoulos used premorbid temperament, course of illness, family history, worsening with
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Table 2 Evolution of the manic-depressive illness from Kraepelin to DSM-5. Kraepelin
DSM-I
DSM-II
DSM-III
DSM-III R
DSM-IV
DSM-IV TR
DSM-5
Manic depressive reaction, manic type Not recognized Not recognized
Manicdepressive illness, manic type1 Not recognized Not recognized
Manic episode
Manic episode
Manic episode
Manic episode
Manic episode
Atypical bipolar disorder Manic episode, with mood congruent/ incongruent psychotic features
Hypomanic episode
Hypomanic episode
Hypomanic episode
Hypomanic episode
Manic episode, with mood congruent/ incongruent psychotic features
Manic episode, with mood congruent/ incongruent psychotic features
Manic episode, with mood congruent/ incongruent psychotic features
Delirious mania (acute confusion) Depressive states
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Manic episode, with mood congruent/ incongruent psychotic features Not recognized
Melancholia simplex (depressed mood, psychomotor inhibition)
Manic depressive reaction, depressive type Manic depressive reaction, depressive type Not recognized
Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Manicdepressive illness, depressive type2 Not recognized
Major depressive episode3, with melancholia
Major depressive episode3, melancholic type
Major depressive Major depressive Major depressive episode3, with episode3, with episode3, with melancholic features melancholic features melancholic features
Not recognized
Not recognized
Major depressive episode3, with catatonic features
Major depressive episode3, with catatonic features
Major depressive episode3, with catatonia
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with psychotic features, mood-congruent
Major depressive episode3, with mood-congruent psychotic features
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with mood-incongruent psychotic features
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with psychotic features, mood-incongruent
Major depressive episode3, with mood-incongruent psychotic features
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Manic states Mania
Hypomania Delusional mania (elaborated delusions and hallucinations)
Melancholic stupor (depressed mood, marked psychomotor inhibition) Melancholia gravis (mood congruent delusions)
Paranoid melancholia (hallucinations and persecutory delusions)
Not recognized
Not Fantastic melancholia (marked hallucinations recognized and interpretative delusions) Delirious melancholia (acute confusion) Mixed states
Not recognized
Depressive mania (depressed mood, flight of ideas, excitement, anxiety) Excited depression (depressed mood, poverty of thought, great restlessness)
Not recognized
Other major Bipolar disorder, mixed affective disorder
Bipolar disorder, mixed
Mixed episode
Mixed episode
Major depressive episode3, with mixed features
Manic depressive reaction, depressed type Not recognized
Manicdepressive illness, depressive type2 Other major affective disorder
Not recognized
Not recognized
Not recognized
Not recognized
Major depressive episode3, with mixed features
Manic episode with psychotic features, mood-incongruent
Manic episode with psychotic features, mood-incongruent
Manic episode, with catatonic features
Manic episode, with catatonic features
Manic episode, with catatonia
Manic depressive reaction, other Not recognized
Other major Manic episode with psychotic features, affective mood-incongruent disorder
Manic episode with psychotic features, mood-incongruent
Manic episode, with catatonic features
Manic episode, with catatonic features
Manic episode, with catatonia
Other major Not recognized affective disorder
Not recognized
Not recognized
Not recognized
Major depressive episode3, with mixed features
Manic depressive reaction, other
Other major Manic episode with psychotic features, affective mood-incongruent disorder
Manic episode with psychotic features, mood-incongruent
Manic episode, with catatonic features
Manic episode, with catatonic features
Manic episode, with catatonia
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Mania with poverty of thought (euphoric mood, poverty of thought, less excitement) Manic stupor (euphoric mood, marked psychomotor inhibition) Depression with flight of ideas (depressed mood, flight of ideas, psychomotor inhibition) Inhibited mania (euphoric mood, flight of ideas, psychomotor inhibition) Fundamental states Manic temperament
Not recognized
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G.L. Faedda et al. / Journal of Affective Disorders 176 (2015) 18–23
Table 2 (continued ) Kraepelin
DSM-I
DSM-II
DSM-III
DSM-III R
DSM-IV
DSM-IV TR
DSM-5
Not recognized Depressive temperament Not recognized
Not recognized Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Not recognized
Dysthymic disorder
Dysthymic disorder
Dysthymic disorder
Dysthymic disorder
Cyclothymic temperament
Not recognized
Irritable temperament
Not recognized
Persistent depressive disorder (dysthymia) Cyclothymic disorder Cyclothymic disorder Cyclothymic disorder Cyclothymic disorder Cyclothymic disorder
Notes: 1) this disorder consists exclusively of manic episodes; 2) this disorder consists exclusively of depressive episodes; 3) major depressive episode applies both to bipolar disorder and major depressive disorder; from DSM-III to DSM-IV TR, bipolar disorder and major depressive disorder have been put together in the mood disorders category; in the DSM-5 they are two separate categories (bipolar and related disorders; depressive disorders).
antidepressant/stimulants treatment and improvement with sedatives and ECT as independent validators of both, the bipolar nature of these episodes and their independent nosological status. He suggested that these mixed symptoms during MDE were often misdiagnosed as agitated depression, and should be regarded as a risk factor for suicide and rapid cycling course of illness. Koukopoulos' conceptualization of mixed states is well within his later proposal of the primacy of mania, here presenting as ‘hypomanic equivalents’ (racing/crowded thoughts, heightened anxiety, aggressive impulses, psychomotor agitation and sleep disturbances) during a depressive episode as important factors in the clinical evolution and treatment response (Koukopoulos and Ghaemi, 2009). The excitatory nature of these symptoms is confirmed by its response to antimanic and or sedative agents; such treatments would instead worsen the clinical picture if its nature was pure depressive. Additionally these excitatory symptoms occurred only after (or increased following) treatment with antidepressants or use of stimulants such as caffeine, amphetamines or cocaine. Additionally, the exclusion of overlapping criteria such as irritability, agitation and distractibility, effectively makes much more difficult to meet diagnostic criteria. In fact, failing to exclude the overlapping symptoms would result in approximately half of the depressive states being reclassified as mixed (Angst et al., 2011). A limitation of this article is the selective but not systematic review of the literature on depressive mixed states. Relatively little research data is currently available for validation of the criteria proposed by Koukopoulos. In the DSM-5, the status of mixed depressive syndromes is more uncertain than before (Koukopoulos et al., 2013). This is likely to further complicate the proper diagnosis and treatment of depressive mixed states ignoring the rich literature clearly indicating the bipolar nature of such common clinical presentations. In summary, Koukopoulos's diagnostic and therapeutic contributions on the psychopathology and treatment of bipolar mixed depression can be summarized as follows:
4.1. Diagnostic contributions 1) Mixed states extend well beyond the DSM criteria currently used in research and practice; besides mania with dysphoric/mixed features, many patients presenting with MDD can experience hypomanic symptoms as in mixed depression. 2) Hypomanic symptoms occurring during MDE are common, representing ¼ outpatients with MDE (33% in women). This finding has been recently replicated (Sani et al., 2014a, 2014b). 3) The clinical presentation of mixed states is similar to certain form of agitated depression. 4) Hypomanic symptoms during MDE increase the risk of suicidal ideation and behaviors. 5) Premorbid temperamental features, especially hyperthymic and cyclothymic temperaments, are often responsible for such mixed depressive presentations.
6) Family history for recurrent depression and bipolar disorders might distinguish such presentations from unipolar depressives. 4.2. Therapeutic contributions 1) The presence of such hypomanic features might explain the worsening of symptoms during antidepressant treatment (except for ECT) even the suicidal ideation/gestures. 2) Discontinuation of antidepressant treatments (other than ECT) often improved the clinical presentation, with decreased agitation, tension or racing thoughts, better sleep and decreased suicidal ideation. 3) The beneficial response to sedatives including benzodiazepins and antipsychotis appears to confirm the excitatory nature of such mixed presentations during bipolar depressive episodes; a recent study found an atypical antipsychotic to be specifically effective for mixed depressive syndromes (Patkar et al., 2012). Role of funding source Nothing declared.
Conflict of interest No conflict declared.
Aknowledgments Nothing to disclose.
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