Mixed States in Their Manifold Forms: Part 2

Psychiatric TimesPsychiatric Times Vol 28 No 4
Volume 28
Issue 4

Mixed depression is defined as a major depressive episode (MDE) with concurrent manic or hypomanic symptoms that are insufficient in number for a patient to meet the criteria for mixed hypomania.

[Editor's Note: This is Part 2 of a 3-part series. Click here for Part 1. Click here for Part 3]

Mixed depression is defined as a major depressive episode (MDE) with concurrent manic or hypomanic symptoms that are insufficient in number for a patient to meet the criteria for mixed hypomania.1-8 As originally defined, euphoria and increased self-esteem were exclusion criteria for mixed depression. The potential scope of mixed depression has recently been expanded by employing the principle that any and all features of hypomania/mania can occur in the context of an MDE.9 This is consistent with Kraeplin’s observations and parallels DSM-IV criteria for mixed episode.10

In this second article on mixed states (see Part 1) I review the literature on the original concept of mixed depression. This phenomenon was first described in a series of outpatients in the midst of an MDE. Symptoms of hypomania, just as one would expect, are more common in mixed depression in outpatients than are those of mania. However, inpatients who meet the criteria for mixed depression can have intradepressive episode features characteristic of frank mania.8

Defining mixed depression

A highly useful and well-validated definition of mixed depression requires the presence of at least 3 symptoms of hypomania, other than elevated mood and increased self-esteem/grandiosity, as defined in DSM-IV in the context of an MDE.1-4 In a consecutive series of outpatients who met the criteria for MDE, Benazzi11 found that defining mixed depression in this way provides sensitivity and specificity for bipolar II disorder of 51.4% and 86.7%, respectively. This indicates that the probability of detecting a patient in the midst of an MDE with bipolar II disorder is only slightly greater than 50% if he or she has mixed depression accompanied by exactly 3 features of hypomania. Using this standard, 49.6% of all cases would be missed. However, a specificity of 86.7% is excellent.

These findings indicate that there is minimal risk of falsely concluding that one’s patient has bipolar II disorder if he has an MDE that includes as few as 3 features of hypomania. Thus, if a patient in the midst of an MDE has 3 features of hypomania in the context of the episode, it is only logical to assume that the patient has or will demonstrate a course characteristic of bipolar II disorder.

An operational definition of mixed depression that requires a cutoff of 4 symptoms of hypomania rather than only 3 would unreasonably decrease sensitivity for the diagnosis of bipolar II disorder and affect a clinically inconsequent rise in specificity. Conversely, defining mixed depression as an MDE contaminated by only 2 features of hypomania would raise sensitivity, but at the expense of a decline in specificity.

The validity of defining mixed depression as entailing the presence of 3 features of hypomania other than elevated mood and inflated self-esteem/grandiosity in the context of an MDE is supported by family history data. The presence of 3 symptoms of hypomania is associated not only with a course-defining bipolar II disorder but also with a higher risk of bipolar disorders among one’s first-degree relatives than a definition requiring fewer than 3 symptoms.1-4

It is both interesting and conceptually important to note that Benazzi12 found that there is a dose-response relationship between the number of intra-MDE symptoms of hypomania and the probability of having a first-degree relative with bipolar illness. Statistical modeling indicated that the likelihood of a patient having a relative with a bipolar disorder increased as the number of symptoms of hypomania in the context of an MDE increased.

Relationship between agitated depression and mixed depression

Published findings also suggest that there is a relationship between agitated depression (ie, psychomotor agitation in the context of an MDE) and mixed depression. Akiskal and colleagues6 reported that 90% of all patients with major depressive disorder who presented with psychomotor agitation met the criteria for mixed depression using the criterion that 3 or more features of hypomania are present within the context of an MDE. The most common features of hypomania that they reported to be present were irritability, racing/crowded thoughts (painfully experienced mental overactivity), hypertalkativeness, and distractibility.

Patients with agitated depression were more likely to have family histories of bipolar disorders than patients with major depressive disorder who did not exhibit psychomotor agitation (24.0% vs 11.5%, respectively; P < .05). Maj and colleagues13 also found that mixed depression commonly occurred in patients with agitated unipolar depression and that it was strongly associated with a family history of bipolarity relative to agitated depression that fell short of the criteria for mixed depression. They concluded that patients with apparent unipolar depression accompanied by psychomotor agitation and manic/hypomanic symptoms fall along the bipolar spectrum.

Should one accept that mixed depression as defined above falls along the bipolar spectrum, it follows that about 70% of those in the midst of an MDE have a bipolar spectrum disorder in the settings in which the topic has been studied to date.14 It is critical to emphasize that this figure is derived primarily from a study of outpatients and applies only if elevated mood and inflated self-esteem/grandiosity are regarded as exclusion criteria for mixed depression.

It is important to recognize that the percentage of all MDEs that meet the criteria for mixed depression may vary depending on clinical setting. For example, the prevalence of MDEs that meet the criteria for mixed depression may differ in general private practices; community mental health clinics, where the chronically and persistently mentally ill are treated; subspecialty clinics in tertiary care centers; and inpatient settings.

Does pure depression exist?

Akiskal and I9 recently ascertained the characteristics of adults in the midst of their first MDE retrospectively. The first MDE generally occurred years before efforts to determine its features. None of the patients in our study had been exposed to medications such as antidepressants and mood stabilizers that might have affected the manifestations of their first episode.

In this study, any and all features characteristic of hypomania/mania-including elevated/euphoric mood and inflated self-esteem/grandiosity-were presumed to be compatible with the presence of a concurrent MDE. This was in contrast to exclusionary rules applied in earlier pivotal studies of mixed depression. Thus, the search for hypomanic/manic features continued even if a patient did not meet Criterion A for hypomania or mania. Criterion A requires that a patient have elevated/expansive or irritable mood. A patient was classified as having only 1 symptom of hypomania or mania if he had both elevated and irritable mood. The DSM-IV convention that racing thoughts and flight of ideas count as 1 symptom within Category B was followed. Similarly, psychomotor agitation and increased goal-directed activity counted as a single symptom if both were present.

Of the 133 patients in the database, only 2 were devoid of a feature of hypomania or mania. Thus, 131 of the MDEs had mixed features. If the results had been affected by recall bias, it would have yielded a false-negative rather than the false-positive reporting of symptoms. One hundred nineteen patients met the criteria for mixed episode, mixed hypomania, or mixed depression as defined as the presence of at least 3 features of hypomania/mania within the context of the MDE.

My colleague and I9 concluded that there was only bipolarity and pseudounipolar disorder present with varying degrees of “mixity” in the sample studied. Mixity refers to the degree of contamination of an MDE by features of hypomania or mania.15 The results of this study suggest that pure depression (ie, depression unscathed by features of hypomania or mania) is extremely rare, and we concluded that the fraction of episodes free of mixed features was, from a conceptual standpoint, inconsequential.

Studies of larger cohorts of patients in the midst of an MDE seen in a variety of clinical settings are required to confirm these findings. The findings may not apply to patients who present with their second or third MDE or to those who have been exposed to medications used to treat disorders of mood. An important strength of this study, however, was the absence of medication-induced artifacts.

The treatment of mixed depression

Mixed depression predicts unresponsiveness to antidepressant monotherapy.2 The results of published studies of the treatment of mixed depression are not yet available, although studies are now ongoing in Europe. However, opinions vary so much that the late Franco Benazzi and I16 proposed alternative methods of managing these states.

Our primary treatment objective was to suppress hypomanic symptoms with mood-stabilizing or antipsychotic agents when treating patients with non–bipolar I mixed depression. Benazzi generally initiated treatment with these medications at low dosages and rapidly titrated the dose according to response. Benazzi emphasized that mixed depression should not be treated with antidepressant monotherapy, given that mixed depression, in his judgment, is unresponsive to monotherapy with antidepressants and because these agents may exacerbate manic and hypomanic symptoms.

Benazzi recommended SSRI therapy (at a modest dosage) when depressive symptoms persist following the disappearance of symptoms of hypomania. If depressive symptoms persist, he would slowly increase the dosage of the antidepressant while observing patients for the emergence of symptoms of hypomania. This method of treatment requires careful monitoring of the patient and frequent visits. Thus, the feasibility of using this method is sensitive to the clinical setting in which one practices. It is practical in the setting of a private practice in which patients can be seen weekly. This was the setting in which Benazzi conducted his research. In contrast, it is not possible to implement this strategy in a large, public sector clinic in which patients cannot be seen weekly.

Once a patient’s symptoms are in remission, the dosing regimen is continued during the acute, continuation, and maintenance phases of treatment. Frequent face-to-face visits remain essential during the continuation phase of treatment.

On the other hand, I treat patients with mixed depression, regardless of the clinical setting, as if they have bipolar II disorder-even if they cannot recall having an episode of hypomania. I try to avoid antidepressants in all phases of treatment unless absolutely necessary, because of the risk of inducing hypomania and concern about the induction of mixed hypomania. Furthermore, there is concern that during the maintenance phase, the ongoing use of antidepressants might destabilize mood and predispose the patient to the onset of rapid cycling. There is also concern that the use of antidepressants during the maintenance phase might increase the risk of insomnia, irritability, anxiety, and restlessness. However, further studies are needed to confirm these hypotheses.

Many patients with mixed depression have histories of refractory depression as evidenced by the failure to respond to treatment with 4 or 5 sequential trials of antidepressants over a period of years. Many have histories of worsening symptoms of affective illness during treatment with these medications, including exacerbation of irritability, sleep disturbance, restlessness, and anxiety. A substantial fraction of patients are dysphoric for a year or more, without any remission of symptoms. Tragically, many have been ill for a decade or longer.

Treatment of mixed depression with an atypical antipsychotic frequently results in remission of symptoms of hypomania within 1 to 2 weeks; however, much lengthier periods of treatment may be required to affect the elimination of the features of hypomania. Dosage regimens similar to those used to treat mania may be required. Until we have the results of trials that assess the efficacy of specific agents and various pharmacological regimens, it is premature to recommend any particular medication or combination of agents for use in patients with mixed depression. The effective use of an atypical agent in and of itself may induce a substantial reduction in distress. In particular, patients with painful crowding of thought and distressful mental overactivity may experience improvement within 2 weeks.

Patients with mixed depression are at high risk for recurrence unless they receive vigorous prophylaxis and the objectives of maintenance anticipated when treatment is initiated. Lamotrigine does not exert acute antidepressant effects nor does it have antimanic properties.17-19 However, it is highly effective when used as prophylaxis during the depression phase of bipolar disorder.20 When marked anxiety is present, and especially if panic attacks are plaguing a patient, a schedule-based regimen of a benzodiazepine with antipanic effects can be prescribed. This triad of an atypical agent, lamotrigine, and a benzodiazepine with antipanic properties is often highly effective.

Treatment with antidepressants should be reserved for relatively rare use. There should be a minimum of 2 weeks after remission of symptoms of hypomania before an antidepressant is added to a patient’s regimen. Additional randomized trials are required to validate any approach to the treatment of mixed depression.

The potential of the effectiveness of lithium in aborting or diminishing the severity of episodes of mixed depression or in preventing their recurrence merits comment. In 1994, Bowden and colleagues21 published an article reporting that divalproex was as effective as lithium in the treatment of acute mania. Perhaps because of the ease of dosing and its tolerability profile, divalproex rapidly replaced lithium as the most commonly used drug to treat this syndrome. Effecting this end was not the objective of the study. Rather, its aim was simply to determine whether divalproex was comparable to lithium in the treatment of mania.

Subsequently, Swann and colleagues22 published the results of a secondary analysis. The results suggested that even a modest degree of pretreatment depressive symptoms is a robust predictor of nonresponse to lithium and a predictor of a superior response to divalproex. Findings from this and other studies have resulted in the decreased use of lithium in the treatment of mixed states. However, lithium still has an important place in the armamentarium for the treatment of mixed states of all types, and it is an effective prophylactic agent for mixed phenomena.




Akiskal HS, Benazzi F. Delineating depressive mixed states: their therapeutic significance.

Clin Approach Bipolar Disord

. 2003;2:41-47.


Benazzi F. Reviewing the diagnostic validity and utility of mixed depression (depressive mixed states).

Eur Psychiatry

. 2008;23:40-48.


Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states.

J Affect Disord

. 2003;73:113-122.


Benazzi F. Family history validation of a definition of mixed depression.

Compr Psychiatry

. 2005;46:159-166.


Benazzi F. Mixed depression: a clinical marker for bipolar-II disorder.

Prog Neuropsychopharmacol Biol Psychiatry

. 2005;29:267-274.


Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy

. J Affect Disord

. 2005;85:245-258.


Goldberg JF, Perlis RH, Bowden CL, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD.

Am J Psychiatry

. 2009;166:173-181.


Sato T, Bottlender R, Schröter A, Möller HJ. Frequency of manic symptoms during depressive episode and unipolar ‘depressive mixed state’ as bipolar spectrum.

Acta Psychiatr Scand

. 2003;107:268-274.


Dilsaver SC, Akiskal HS. Does unipolar depression exist?

J Affect Disord

. In press.


Kraepelin E.

Manic Depressive Insanity and Paranoia

. Edinburgh: E & S Livingstone; 1921.


Benazzi F. Which could be a clinically useful definition of depressive mixed state?

Prog Neuropsychopharmacol Biol Psychiatry

. 2002;26:1105-1111.


Benazzi F. The continuum/spectrum concept of mood disorders: is mixed depression the basic link?

Eur Arch Psychiatry Clin Neurosci

. 2006;256:512-515.


Maj M, Pirozzi R, Magliano L, et al. Agitated “unipolar” major depression: prevalence, phenomenology, and outcome.

J Clin Psychiatry

. 2006;67:712-719.


Benazzi F. Bipolar disorder-focus on bipolar II disorder and mixed depression.


. 2007;369:935-945.


Akiskal HS, Hantouche EG, Bourgeois ML, et al. Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from the French national study (EPIMAN).

J Affect Disord

. 1998;50:175-186.


Dilsaver SC, Benazzi F. Treating depressive mixed states in bipolar disorders.

J Clin Psychiatry

. 2008;69:e23.


Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials.

Bipolar Disord

. 2008;10:323-333.


Ghaemi SN, Shirzadi AA, Filkowski M. Publication bias and the pharmaceutical industry: the case of lamotrigine in bipolar disorder.

Medscape J Med

. 2008;10:211.


Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder.

J Clin Psychiatry

. 2004;65:432-441.


Malhi GS, Adams D, Berk M. Medicating mood with maintenance in mind: bipolar depression pharmacotherapy.

Bipolar Disord

. 2009;11(suppl 2):55-76.


Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group [published correction appears in


. 1994;271:1830].


. 1994;271:918-924.


Swann AC, Bowden CL, Morris D, et al. Depression during mania. Treatment response to lithium or divalproex.

Arch Gen Psychiatry

. 1997;54:37-42.

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