Introduction
Depressive mixed states (DMX) are phenomenologically different from pure major depression due to the presence of excitatory (hypomanic) symptoms, and they have been extensively characterized by the works of Emil Kraepelin and Wilhelm Weygandt. In the classic medical literature, DMX, and mixed states in general, have always been considered as part of manic-depressive illness.
DMX are characterized by motor agitation (such as pacing; handwringing; inability to sit still; pulling or rubbing hair, skin, clothing, or other objects; outburst of complaining or shouting), inner psychic tension (which makes the patient very anxious and fearful), racing or crowded thoughts (which generally are not expressed verbally), talkativeness, mood lability/irritability, inhibition of purposeful activity, and marked anhedonia.Reference Koukopoulos, Sani, Koukopoulos, Manfredi, Pacchiarotti and Girardi 1 Some DMX present with pronounced psychomotor agitation, while in others anxiety and/or inner psychic agitation dominate the clinical picture.
Although the Research Diagnostic CriteriaReference Spitzer, Endicott and Robins 2 recognized and described agitated major depression as a separate category, the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) and following editions did not consider irritability, psychomotor agitation, and distractibility as hypomanic symptoms, but rather as depressive symptoms.
The introduction of the Mixed Feature Specifier in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) represents a very significant conceptual shift that affects nosology, research, and clinical practice. In order to understand this shift, it is necessary to appreciate the phenomenology of mixed states as well as the changes in their classification across successive editions of the DSM (Table 1).
Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for mixed states
The clinical characteristics of DMX are very similar to those of bipolar mixed states.Reference Swann, Lafer and Perugi 3 Bipolar mixed states, including DMX, are found more often in patients with greater rates of recurrence, complex comorbidities, and suicidality.Reference Koukopoulos, Sani, Koukopoulos, Manfredi, Pacchiarotti and Girardi 1 , Reference Koukopoulos, Faedda, Proietti, D’Amico, de Pisa and Simonetto 4 , Reference Sani, Vöhringer and Napoletano 5 A history of past mixed states also increases the risk of having future mixed states, and is usually associated with poor treatment response and outcome. Prospective and retrospective studies have confirmed that bipolar mixed states are difficult to treat, with poor response to monotherapy with antidepressants or mood stabilizers and improvement with combined treatment with antipsychotics and mood stabilizers.Reference Koukopoulos, Faedda, Proietti, D’Amico, de Pisa and Simonetto 4 , Reference Suppes, Silva and Cucchiaro 6
The Third, Third Revised, Fourth, and Fourth Text Revision editions of the DSM all recognized a narrow definition of mixed states as “mixed mania,” a period of time (at least 1 week) in which the criteria are met for both a manic episode and a major depressive episode. However, it is now clear that among mixed states, most do not meet full criteria for mania.Reference Sani, Vöhringer and Napoletano 5
With the introduction in the DSM-5 of the Mixed Feature Specifier, which is applicable to hypomanic, manic, and depressive episodes, both in major depressive disorder (MDD) and bipolar disorder (BD) (Table 1), hypomanic symptoms are no longer specific to BD. This change might allow for a more frequent recognition of mixed features during episodes of major depression, but does not guarantee appropriate treatment.
Since most of the information on the use of antidepressants in DMX is based on bipolar subjects, we will review evidence regarding the safety, tolerability, and efficacy of antidepressant drugs for patients with symptoms now included in the Mixed Features Specifier definition.
Clinical Characteristics of Major Depression with Mixed Features
The presence of hypomanic symptoms during an episode of depression has been described in the phenomenology of mixed states since the 19th century. Up to 2013, most data on mixed states was collected in patients with BDReference Swann, Lafer and Perugi 3 ; few studies investigated the role of intradepressive hypomanic symptoms in patients with MDD.
DMX, in contrast to pure major depression, are characterized by earlier age at onset, high frequency of depressive recurrences, longer episode duration, increased risk of suicide attempts, psychotic symptoms, comorbid anxiety and substance abuse disorders, and antidepressants-induced mania/hypomania, as well as greater illness severity, functional disability, and poorer prognosis.Reference Smith, Forty and Russell 7 – Reference Perugi, Angst and Azorin 12
Among those patients with MDD, 22% to 50% have had at least 1 manic symptom, and 7% to 23% had 3 or more manic symptoms; similarly, in BD-I and BD-II patients, more than 50% experience at least 1 manic symptom and 10–16% at least 3 manic symptoms during depression.Reference Koukopoulos and Sani 13 Additionally, the presence of hypomanic symptoms during major depression has been found to be a significant risk factor for the development of BD in prospective studies.Reference Faedda, Marangoni and Serra 14
In the DSM-5 (Table 1), core features of DMX, such as irritability, distractibility, and psychomotor agitation, have been excluded from the Mixed Features Specifier criteria because they are present both in MDE and manic episode; this decision is questionable, however, since clinical studies show that these core hypomanic symptoms are very frequent compared to euphoric/grandiose mood in patients with DMX.
Koukopoulos et al Reference Koukopoulos and Sani 13 systematically reviewed the papers used as reference by the DSM-5 Mood Disorders Work Group in defining the symptoms of major depression with mixed features. They found that the clinical picture proposed by DSM-5 criteria is extremely rare in DMX and does not target the great suffering linked to the disorder. In fact, the most common intradepressive hypomanic symptoms reported in the papers were irritability, motor agitation/restlessness, distractibility, racing thoughts, and flight of ideas. Less than 10% of the patients reported euphoric mood or inflated self-esteem/grandiosity. Additionally, some recent studiesReference Suppes, Silva and Cucchiaro 6 , Reference Perugi, Angst and Azorin 12 have confirmed the clinical characteristics of major depression with mixed features.
Treatment Issues in Major Depression with Mixed Features
Antidepressants
The safety, tolerability, and side effect profile of antidepressants for the treatment of the Mixed Features Specifier is limited to retrospective data obtained in BD patients.Reference Perlis, Ostacher and Goldberg 15 – Reference Akiskal, Benazzi, Perugi and Rihmer 17
Using the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) data, Goldberg et al Reference Goldberg, Perlis and Ghaemi 18 examined the 3-month outcomes of patients with bipolar mixed depression who were treated with antidepressants plus mood stabilizing drugs. Adjunctive antidepressant use did not reduce time to recovery relative to treatment with mood stabilizers alone, and was associated with significantly higher mania symptom severity at the 3-month follow-up.
In an independent sample, the Bipolar Collaborative Network, Frye et al Reference Frye, Helleman and McElroy 16 found that a subset of baseline hypomanic symptoms predicted treatment-emergent hypomania in bipolar depression: increased motor activity, speech disorder, distractibility, and racing thoughts.
Further adding to this evidence, in the STEP-BD,Reference Perlis, Ostacher and Goldberg 15 3 clinical features were identified that conferred a greater risk of switch in antidepressant exposed vs unexposed individuals: history of suicide attempt, younger age, and bipolar-I subtype; also, a greater number of past depressive episodes, greater mania severity, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants were risk factors for treatment-emergent mania.
The presence of a pharmacological or iatrogenic precipitant to DMX is well illustrated by Koukopoulos et al.Reference Koukopoulos, Sani, Koukopoulos, Manfredi, Pacchiarotti and Girardi 1 In a large chart review study, in 56% of the cases of agitated depression, with psychic/motor agitation, insomnia, impulsivity, and suicidality, the onset of agitation was associated with pharmacological treatments, mainly antidepressants, and took place either immediately or within a few days to a few weeks. Such states can be managed effectively by discontinuing antidepressants and using mood stabilizers or other antimanic agents.Reference Koukopoulos, Faedda, Proietti, D’Amico, de Pisa and Simonetto 4 The contribution of antidepressants to the development or worsening of suicidal ideation and behaviors has been attributed to disinhibition and impulsivity.Reference Fornaro, Martino, De Pasquale and Moussaoui 19
These findings were confirmed in a cohort of 219 consecutively assessed outpatients with DMX, who were diagnosed using Koukopoulos’s criteria: a diagnosis of BD type-II, greater depression severity and older age at index episodes were predictors of DMX, and antidepressants were associated with half of the cases diagnosed with DMX.Reference Sani, Napoletano and Vöhringer 20
Additional data were provided in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.Reference Perlis, Cusin and Fava 21 Among 2397 subjects with MDD, 18.7% endorsed at least 2 of 6 self-reported mania subscale items of the Psychiatric Diagnosis Screening Questionnaire: the presence of expansive mood and cheerfulness were associated with a greater likelihood of remission, pointing to the cycling potential of these depressive states compared to those subjects with MDD without such mixed features. Indeed, this study systematically excluded cases of overlapping manifestations, such as increased psychomotor agitation, irritability, and distractibility, therefore selecting for subjects with a “less severe” illness.Reference Perlis, Cusin and Fava 21
The International Society for Bipolar Disorder Task Force on Antidepressant use in BDReference Pacchiarotti, Bond and Baldessarini 22 recommends that (1) antidepressants should be avoided during manic and depressive episodes with mixed features; (2) antidepressants should be avoided in bipolar patients with predominantly mixed states; (3) antidepressants should be discontinued in patients currently experiencing a mixed state.
Antipsychotics
Atypical antipsychotics have been shown to have mood-stabilizing properties, and selected agents have demonstrated antidepressant efficacy in bipolar depression. Currently quetiapine, olanzapine + fluoxetine, and lurasidone have been approved in the US for the treatment of major depressive episodes in BD-I, while aripiprazole and olanzapine + fluoxetine have been approved also for treatment-resistant MDD.
Additional evidence of efficacy comes from a recent systematic review and meta-analysis of placebo-controlled clinical trials of atypical antipsychotics in bipolar depression with mixed features that demonstrated significant improvements in both Montgomery–Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores.Reference Fornaro, Stubbs and De Berardis 23 Finally, a randomized, double-blind, placebo-controlled study found lurasidone to be effective and well tolerated in patients with MDD with mixed features.Reference Suppes, Silva and Cucchiaro 6
Discussion
In summary, the treatment of intradepressive hypomanic symptoms has been limited to (1) bipolar depression and (2) depressive episodes with mixed features. It appears that antidepressants alone have limited efficacy in bipolar depression,Reference Sachs, Nierenberg and Calabrese 24 but they have the potential for inducing, maintaining, or worsening mixed features during depressive episodes in BD.Reference Koukopoulos, Sani, Koukopoulos, Manfredi, Pacchiarotti and Girardi 1 , Reference Koukopoulos, Faedda, Proietti, D’Amico, de Pisa and Simonetto 4 , Reference Frye, Helleman and McElroy 16 , Reference Goldberg, Perlis and Ghaemi 18 , Reference Sani, Napoletano and Vöhringer 20 , Reference Pacchiarotti, Bond and Baldessarini 22 ,25 On the other hand, preliminary evidence supports the effective use of atypical antipsychotics in the treatment of DMX.
It must be noted that many of the changes introduced in the editions of DSM were not based on evidence, and in the case of the Mixed Features Specifier, were not always driven by data.Reference Koukopoulos, Sani and Ghaemi 25
These changes in the nosology of mood disorders also led to an increase in the heterogeneity of major depression—a diagnostic category used in all clinical trials. By combining heterogeneous conditions, such as pure depression and DMX, in the same diagnostic category, the DSM has consistently ignored all the depressive mixed states described in the clinical literature until DSM-5.
Such heterogeneity helps to explain the variety of clinical outcomes following treatment with antidepressant agents. While a majority of patients with major depression benefits from antidepressant treatment, a significant minority does not respond, or experiences severe adverse psychiatric symptoms beyond usually reported side effects. Even the presence of depressive and manic mixed states precipitated by the use of antidepressants—a phenomenon reported as far back as the discovery of antidepressant agentsReference Michaux, Saulnier and Bureau 26 – Reference Glassman 28 —was not sufficient to raise awareness and research interests in these conditions.
Some patients (possibly undiagnosed bipolar, or prone to severe side effects for metabolic causes) can experience short or prolonged periods of hypomania. Such states, if induced by the treatment, are referred to as iatrogenic. Some patients cycle rapidly either spontaneously or during exposure to antidepressants, and might enter prolonged periods of dysphoric agitation with impulsive self-harm, suicidal ideation, and gestures. In such cases, the discontinuation of antidepressants, or adjunctive treatment with typical or atypical antipsychotics, sedatives, or ECT, is usually helpful or therapeutic.Reference Koukopoulos, Faedda, Proietti, D’Amico, de Pisa and Simonetto 4 , Reference Suppes, Silva and Cucchiaro 6 , Reference Wehr and Goodwin 29 – Reference Faedda, Marangoni and Reginaldi 33
In the DSM-5, the status of DMX is more uncertain than before.Reference Koukopoulos and Sani 13 This is likely to further complicate the proper diagnosis and treatment of DMX, ignoring the rich literature clearly indicating the bipolar nature of such common clinical presentations. The recent changes to the DSM classification have created a new category of patients experiencing MDD along with mixed features (hypomanic symptoms) who do not meet criteria for BD, de facto unlinking mixed features (hypomanic symptoms) from BD. This makes it possible and likely that patients with intradepressive hypomanic symptoms will be exposed to antidepressants, effectively circumventing the safety guidelines of the US Food and Drug Administration (FDA), which require demonstrated safety, efficacy, and tolerability before approval for a specific indication. As patients with BD experience significant depressive morbidity, the safety of antidepressant treatments in the acute and maintenance treatment of BD remains largely unexplored.
In the acute management of BD, and especially DMX, the use of antidepressants must be decided on an individual basis, carefully weighing the risks and benefits. Careful, frequent monitoring during antidepressant treatment, especially titration and discontinuation, should always be a part of the more comprehensive approach to the management of depressive symptomatology, within the patients’ unique medical, psychological, and social circumstances. A longitudinal assessment of the effect of antidepressant treatments on morbidity and mortality seems to offer the best opportunities to identify protective and risk factors to improve both short- and long-term outcomes.
Conclusion
In summary, diagnostic and therapeutic contributions on the psychopathology and treatment of DMX can be summarized as follows:
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∙ The clinical features of DMX and agitated depression can overlap, and intradepressive hypomanic symptoms must be considered.
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∙ Hypomanic symptoms occurring during MDE are common and have been extensively reported in BD-I and BD-II.
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∙ Hypomanic symptoms during MDE increase the risk of manic switch with antidepressant, rapid cycling, and also suicidal ideation and behaviors.
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∙ The presence of hypomanic features might explain the infrequent occurrence during antidepressant treatment of a worsening of impulsivity, aggression, and suicidal ideation/gestures.
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∙ Great caution should be used when prescribing antidepressants monotherapy and even in combination with atypical antipsychotics, especially in depressed patients exhibiting such hypomanic features.
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∙ In the occurrence of a mixed state precipitated by antidepressant, discontinuation of treatment often improves the clinical presentation.
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∙ The beneficial response to sedatives including mood stabilizers and antipsychotics appears to confirm the excitatory nature of such mixed presentations during bipolar depressive episodes.
Disclosures
The authors do not have anything to disclose.
