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        Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV)
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Summary

The DSM system has never acknowledged a central position for mixed states; thus, mixed depressions have been almost completely neglected for decades. Now, DSM-5 is proposing diagnostic criteria for depression with mixed features that will lead to more misdiagnosis and inadequate treatment of this syndrome. Different criteria, based on empirically stronger evidence than exists for the DSM-5 criteria, should be adopted.

Footnotes

Declaration of interest

In the past 12 months, S.N.G. has received research grants from Pfizer and Takeda Pharmaceuticals, and has provided research consultation to Sunovion Pharmaceuticals.

The great British psychiatrist Aubrey Lewis once emphasised that a legitimate psychiatric nosology needs to be both useful and valid; one or the other is insufficient. Reference Lewis1 It appears that validity is less and less relevant to DSM revisions; utility has become the primary concern, especially a strong theoretical desire to avoid expanding psychiatric diagnoses so as to avoid ‘overdiagnosis’ of mental illnesses in the general population. Reference Frances2 A clinically common and important example of this prioritisation of ‘pragmatic’ concerns over clinical reality is the phenomenon of mixed states in depression. Reference Frances2

DSM: the rejection of mixed states

In 1980, DSM-III 3 divided Kraepelin's broad concept of manic-depressive insanity (MDI) into two parts: bipolar disorder and major depressive disorder (MDD). This was not Kraepelin's approach, Reference Goodwin and Jamison4 which was that all recurrent mood illness, whether depressive or manic, was one illness - MDI. If a patient had ten depressive episodes, it was MDI; if a patient had ten manic episodes, it was MDI. The polarity - depression versus mania - did not matter. The recurrence of episodes, alternating with normality (or subsyndromal symptoms), was diagnostic. This is how Kraepelin phrased it:

‘The course of manic-depressive insanity is marked by a recurrence of attacks separated by lucid intervals… It seldom happens that all are of the same type; at some time or other a depressive attack is sure to appear… several depressive attacks may recur before a manic attack appears; in other words, the occurrence of several attacks of one type to the exclusion of other types indicates that the greater number of attacks throughout life will be of the same character.’ Reference Krapelin and Diefendorf5

As can be seen from this passage, Kraepelin clearly emphasised the importance of recurrence in general, rather than making a specific pole diagnostic.

Half a century after Kraepelin, Leonhard argued for polarity as the basis of diagnosis, distinguishing patients with unipolar disorder from those with bipolar disorder according to genetic and course findings - the bipolar/unipolar dichotomy. Reference Leonhard6 Later in the DSM-III process, Reference Shorter7 mild, chronic versions of depression were aligned with Leonhard's severe episodic unipolar depression - producing that giant mish-mash entity of ‘major depressive disorder’. In this sense, then, the DSM-III nosology of mood is neo-Leonhardian, and not Kraepelinian.

There is an important consequence of this historical evolution. Because DSM-III insisted on polarity as the basis of diagnosis, it had to explain away mixed-mood states. Mixed states, by definition, involve the mixing of poles, which thus means that mood poles cannot be sufficiently distinguished to form the basis for diagnosis. If mixed states are common, then the entire DSM system for mood disorders falls apart. Kraepelin thought mixed states were frequent forms of mood episodes, hence the invalidity of polarity as the basis for diagnosing mood illnesses. (One must acknowledge that Kraepelin saw severely ill patients with psychosis in mental asylums; today's out-patient practice setting is different, yet recent studies often are consistent with many of Kraepelin's observations.)

According to DSM-III and DSM-IV, 8 mixed states were seen as rare; this is because those diagnostic criteria made it difficult to diagnose them. This is most clear in DSM-IV, where mixed-mood episodes were narrowed compared with prior definitions by requiring the presence of full manic and depressive episodes at the same time. (These DSM-IV narrow diagnostic criteria for mixed states were not based on any scientific evidence.) This high threshold is met, according to empirical research, by only about 10% of mood episodes. Reference Goodwin and Jamison4

Two decades of research since DSM-IV demonstrates the scientific limits of the DSM neo-Leonhardian error of ignoring mixed states. Yet, in acknowledging this evidence, DSM-5 may make the problem worse, because it proposes a new definition of mixed features in depression that is, once again, not based on empirical evidence - but, rather, on ‘pragmatic’ judgements.

DSM-5: the loss of agitation

The key problem with mixed depression in the DSM system is the insistence that the symptom of psychomotor agitation is diagnostically non-specific. This opinion is a matter of faith, assumed, rather than proven, within the DSM system. Since DSM-III, agitation has been listed as just part of the fifth criterion for a major depressive episode: ‘psychomotor agitation or retardation nearly every day’. This relegation of psychomotor agitation to a subcriterion has resulted in a clinical practice where the same diagnosis, major depression, is given to an extremely agitated person as well as to a person with extreme psychomotor retardation.

The DSM-5 task force made the error of combining manic and depressive symptoms only where those symptoms do not overlap. This ‘non-overlapping’ criterion means that psychomotor agitation is excluded as a criterion of mixed features, as is irritability and distractibility (www.dsm5.org). Thus, DSM-5 defines mixed features of MDD as the presence of major depressive episodes with, most of the time during the episode, three or more of the following: euphoric mood, decreased need for sleep, grandiosity, flight of ideas, talkativeness, increased goal-directed activities and impulsive pleasurable behaviour with potential for painful consequences.

Mixed depression, in our research and experience as well as that of many others, Reference Maj, Pirozzi, Magliano and Bartoli9,Reference Pacchiarotti, Mazzarini, Kotzalidis, Valentí, Nivoli and Sani10 is often characterised by markedly irritable mood and psychic or psychomotor agitation - the exact features excluded in DSM-5. This would be like proposing a new definition for migraine headaches, but excluding symptoms of pain in the head. Of course, one can have pain in the head from other conditions besides migraine, but why should this be a reason to exclude that symptom entirely?

Based on already available evidence, this DSM-5 approach can be demonstrably proven to be scientifically invalid. By requiring euphoric mood, along with depression (a logical contradiction) and excluding psychomotor agitation as diagnostically relevant, DSM-5 creates a clinical construct that is nowhere to be found. In empirical studies, the frequency of mixed-mood states similar to the DSM-5 definition ranges from 0 to 12%. Reference Koukopoulos and Sani11

In contrast, using a definition that includes irritability, psychic or psychomotor agitation as central features of mixed depression, we and others have found frequencies ranging from 33 to 47% in replicated, large studies of patients with mood disorders. Reference Angst, Azorin, Bowden, Perugi, Vieta and Gamma12,Reference Koukopoulos, Sani, Koukopoulos, Manfredi, Pacchiarotti and Girardi13 In our clinical practice, we have seen flight of ideas and talkativeness frequently in mixed depression, but the other five DSM-5 criteria are extremely rare, if ever present.

The verdict of history should also not be ignored. In Kraepelin's careful descriptions, he described two forms of mixed depression: excited depression and depression with flight of ideas. Reference Kraepelin14 Wilhelm Weygandt, in his famous 1899 monograph on mixed states, considered mixed states to be the most common version of manic-depressive illness, as recently analysed, occurring in 64% of patients at the Heidelberg clinic. Reference Salvatore, Baldessarini, Centorrino, Egli, Albert and Gerhard15 Weygandt saw mixed states as an association of depressed mood with psychomotor excitement and flight of ideas, often with agitation. He mentioned elevated mood only in cases of a shift to pure or mixed manic/hypomanic states. Reference Salvatore, Baldessarini, Centorrino, Egli, Albert and Gerhard15 In the writings of the classical authors (with two millennia of clinical experience) there is no mention of five of seven (excluding pressured speech and flight of ideas) DSM-5 mixed criteria.

Defining mixed depression scientifically

In our view, mixed depression does not mean DSM-defined manic and depressive symptoms happening simultaneously. It involves marked psychomotor agitation, inner anguish and irritability being central features of a depressive episode. The DSM-like manic symptoms, such as expansive mood, are sometimes reported along with depressive symptoms, but these relatively uncommon and brief mood states may be better conceptualised as mixed hypomania, rather than the common, longer duration states of mixed depression.

We believe it is a scientific and clinical error to exclude ‘overlapping’ mood symptoms from DSM-5 mixed features. Mixed states are frequent, and validly diagnosing and treating them is central to the practice of psychiatry. Reference Koukopoulos and Ghaemi16 Yet our current nosology practically ignores mixed states. The DSM-5 criteria, as they stand now, will make the scientifically valid diagnosis of mixed depression impossible, and we think that this will have severe consequences for patients. Our experience and research indicates that antidepressants are particularly harmful, and antipsychotics particularly useful, in mixed depression. Reference Patkar, Gilmer, Pae, Vöhringer, Ziffra and Pirok17 By not capturing these patients in the restrictive DSM-5 definition, such patients will receive antidepressants, as they do now, which will worsen the agitation of this condition, and increase risk of suicide.

We propose, for depressive syndromes with psychomotor agitation, the traditional name of ‘agitated depression’ as in the original Research Diagnostic Criteria; Reference Spitzer, Endicott and Robins18 the presence of at least two of the following manifestations of psychomotor agitation (not mere subjective anxiety) for several days during the current depressive episode: pacing; handwringing; being unable to sit still; pulling or rubbing on hair, skin, clothing or other objects; outburst of complaining or shouting; and overtalkativeness.

For mixed depressive syndromes without motor agitation, we propose the name ‘mixed depression’. Along with a major depressive episode, at least three of the following symptoms must be present: inner tension/agitation, racing or crowded thoughts, irritability or unprovoked feeling of rage, absence of signs of retardation, talkativeness, dramatic description of suffering or frequent spells of weeping, mood lability and marked emotional reactivity, and early insomnia. Reference Koukopoulos, Sani, Koukopoulos, Manfredi, Pacchiarotti and Girardi13

Mixed depression deserves its own diagnostic identity, with inner psychic agitation as its central feature, even if the DSM system needs to be overhauled in the process. Only then can we meet Aubrey Lewis' challenge to be both useful and valid in our nosology.

References

1 Lewis, A. States of depression: their clinical and aetiological differentiation. BMJ 1938: 2: 875–8.
2 Frances, A. DSM in philosophyland: curioser and curioser. AAPP Bull 2010; 17: 17 (http://alien.dowling.edu/∼cperring/aapp/bulletin.htm).
3 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (3rd edn) (DSM–IIII). APA, 1980.
4 Goodwin, F, Jamison, K. Manic Depressive Illness (2nd edn): 98. Oxford University Press, 2007.
5 Krapelin, E. Clinical Psychiatry: A Text-Book for Students and Physicians (trans Diefendorf, AR): 412. Macmillan, 1915.
6 Leonhard, K. Aufsteilung der endogenen Psychosen und ihre differenzierte Ätiologie [Distribution of Endogenous Psychoses and their Differentiated Aetiology]. Akademic-Verlag, 1957.
7 Shorter, E. Before Prozac: The Troubled History of Mood Disorders in Psychiatry. Oxford University Press, 2007.
8 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). APA, 1994.
9 Maj, M, Pirozzi, R, Magliano, L, Bartoli, L. Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome. Am J Psychiatry 2003; 160: 2134–40.
10 Pacchiarotti, I, Mazzarini, L, Kotzalidis, GD, Valentí, M, Nivoli, AM, Sani, G, et al Mania and depression. Mixed, not stirred. J Affect Disord 2011; 133: 105–13.
11 Koukopoulos, A, Sani, G. DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand (in press).
12 Angst, J, Azorin, JM, Bowden, CL, Perugi, G, Vieta, E, Gamma, A, et al Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch Gen Psychiatry 2011; 68: 791–8.
13 Koukopoulos, A, Sani, G, Koukopoulos, AE, Manfredi, G, Pacchiarotti, I, Girardi, P. Melancholia agitata and mixed depression. Acta Psychiatr Scand Suppl 2007; 433: 50–7.
14 Kraepelin, E. Psychiatrie (8th edn). Barth, 1913.
15 Salvatore, P, Baldessarini, RJ, Centorrino, F, Egli, S, Albert, M, Gerhard, A, et al Weygandt's on the mixed states of manic–depressive insanity: a translation and commentary on its significance in the evolution of the concept of bipolar disorder. Harv Rev Psychiatry 2002; 10: 255–75.
16 Koukopoulos, A, Ghaemi, SN. The primacy of mania: a reconsideration of mood disorders. Eur Psychiatry 2009; 24: 125–34.
17 Patkar, A, Gilmer, W, Pae, C, Vöhringer, P, Ziffra, M, Pirok, E, et al A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS One 2012; 7: e34757.
18 Spitzer, RL, Endicott, J, Robins, E. Research Diagnostic Criteria (RDC). Biometrics Research, Evaluation Section, New York State Psychiatric Institute, 1978.