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Mixed features in bipolar disorder

Published online by Cambridge University Press:  29 December 2016

Eva Solé ,
Marina Garriga ,
Marc Valentí  and
Eduard Vieta
Eva Solé
Affiliation:
Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain
Marina Garriga
Affiliation:
Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain
Marc Valentí
Affiliation:
Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain
Eduard Vieta*
Affiliation:
Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain
*
*Address for correspondence: Eduard Vieta, Hospital Clinic, 170 Villarroel Street, 08036 Barcelona, Catalonia, Spain. (Email: evieta@clinic.ub.es)
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Abstract

Mixed affective states, defined as the coexistence of depressive and manic symptoms, are complex presentations of manic-depressive illness that represent a challenge for clinicians at the levels of diagnosis, classification, and pharmacological treatment. The evidence shows that patients with bipolar disorder who have manic/hypomanic or depressive episodes with mixed features tend to have a more severe form of bipolar disorder along with a worse course of illness and higher rates of comorbid conditions than those with non-mixed presentations. In the updated Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5), the definition of “mixed episode” has been removed, and subthreshold nonoverlapping symptoms of the opposite pole are captured using a “with mixed features” specifier applied to manic, hypomanic, and major depressive episodes. However, the list of symptoms proposed in the DSM–5 specifier has been widely criticized, because it includes typical manic symptoms (such as elevated mood and grandiosity) that are rare among patients with mixed depression, while excluding symptoms (such as irritability, psychomotor agitation, and distractibility) that are frequently reported in these patients. With the new classification, mixed depressive episodes are three times more common in bipolar II compared with unipolar depression, which partly contributes to the increased risk of suicide observed in bipolar depression compared to unipolar depression. Therefore, a specific diagnostic category would imply an increased diagnostic sensitivity, would help to foster early identification of symptoms and ensure specific treatment, as well as play a role in suicide prevention in this population.

Keywords

Mixed statesdepressionbipolar disorderDSM–5suicide
Type
Opinions
Information
CNS Spectrums , Volume 22 , Issue 2: Theme: Mixed features in major depressive episodes , April 2017 , pp. 134 - 140
Copyright
© Cambridge University Press 2017 

Introduction

Mixed affective states, defined as the coexistence of depressive and manic symptoms, are complex presentations of manic-depressive illness that represent a challenge for clinicians at the diagnosis, classification, and pharmacological treatment levels.Reference Vieta and Valentí 1 , Reference Undurraga, Baldessarini and Valentí 2 Compared to patients with bipolar disorder (BD) who have pure manic/hypomanic or depressive episodes, the presence of mixed-mood states in patients with BD is associated with a different set of clinical features—such as an earlier age at onset, increased frequency of psychotic symptoms, major risk of suicide, higher rates of comorbidities, longer time to achieve remission, and consequently a more severe course and prognosis of the disease.Reference Shim, Woo and Bahk 3

According to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revision; DSM–IV–TR), the diagnosis of a mixed episode only applied to patients with BD type I who had manic and depressive symptoms simultaneously. 5 Therefore, the DSM–IV–TR criteria for mixed states in BD were too narrow, and many patients who met the clinical criteria for this state were excluded from the definition of mixed states and were finally labeled “BD unspecified.” In the updated Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5), the definition of “mixed episode” has been removed, and subthreshold nonoverlapping symptoms of the opposite pole are captured using a “with mixed features” specifier applied to manic episodes and major depressive episodes (MDEs). 6 These changes reflect a wider use of the specifier “with mixed features” that may be applied to both polarities of BD and are likely to play a substantial role in several fields: epidemiology, diagnosis, treatment, research, and education.Reference Vieta and Valentí 1

The present article aims to provide an actualized review on defining the evolution, epidemiology, and clinical relevance of mixed affective states, with a view to supporting clinicians and investigators in resolving the different challenges associated with implementation of this clinical entity.

Evolution of the Concept

In the first century of the Common Era, Aretaeus of Cappadocia proposed the first description of manic-depressive illness as a single disease with two opposite constellations of symptoms.Reference Marneros and Goodwin 7 A more modern concept of mixed states was introduced by Kraepelin and Weygandt in 1899 with the simultaneous contemporary presence of manic and depressive features. This clinical entity, named “mixed states,” was classified into six different subtypes based on substitution of ≥1 of the key symptoms of mania with ≥1 of the key symptoms of depression, and vice versa.Reference Vieta and Valentí 1 The broad definition of “mixed states” described by Kraepelin and Weygandt has been narrowing since then and is now categorized in the DSM–IV–TR.

With the DSM classifications, the syndromes and mental disorders based on categorical diagnostic criteria defined in the DSM–IV–TR have led to easy implementation and improved reliability of mental-health diagnoses. However, as a result of this categorization, multiple diagnoses have become the norm, with high rates of cooccurrence of symptoms and lifetime comorbidity.Reference Wittchen, Höfler, Gloster, Craske and Beesdo 8 Moreover, these restrictive categorical and bidimensional DSM criteria undermine the existence of subsyndromal mixed states and obscure the fact that, in clinical practice, the most prevalent clinical presentation of mixed episodes is the presence of a few concomitant symptoms of the opposite affective polarity,Reference Goldberg, Perlis and Bowden 9 , Reference Swann, Moeller, Steinberg, Schneider, Barratt and Dougherty 10 even though such other symptoms as severe anxiety, prolonged emotional instability, psychotic experiences, and disorganized behavior may be frequent.Reference Perugi and Akiskal 11 This is a recognized problem that has been considered to be associated with a loss of diagnostic validity.Reference Lecrubier 12

In this regard, and with the aim of improving this diagnostic approach, the new DSM–5 6 intended to review and reorient these categorical criteria to a dimensional diagnostic approach that includes “mixed categorical dimensions.”Reference Wittchen, Höfler, Gloster, Craske and Beesdo 8

Epidemiology

Mixed states are common in BD,Reference Benazzi 15 but the existence of different definitions affects the measure of their prevalence across different studies. For instance, using the DSM–5 “with mixed features” specifier may increase the prevalence of manic, hypomanic, or depressive episodes while decreasing the prevalence of “BD unspecified,” which would indicate that prevalence based on the strict definition of mixed states in DSM–IV–TR is unrealistic.Reference Vieta and Valentí 1 In the case of mania with mixed symptoms, and taking into account the narrow definitions of the International Classification of Diseases (ICD–10) and the DSM–III/IV, prevalence rates vary between studies from 6.7 to 28%, while this number rises to 66% when broader definitions are employed.Reference Akiskal, Akiskal and Lancrenon 16 In a cross-sectional multisite study, Vieta and Morralla17 reported a 9% prevalence of mixed states according to the ICD–10 criteria, 13% according to the DSM–IV–TR, and 23% according to a regular medical practitioner’s assessment. Despite the fact that most studies agree that there is no difference between prevalence of mixed depression based on gender,Reference Benazzi 15 – Reference Benazzi 17 some prevalence studies report a higher rate among women (63–69%).Reference Benazzi 18

Depressive mixed states have been less well-studied, and reported rates range from 20 to 70%, depending on study setting, population type, and the use of a broad or narrow definition of mixed states.Reference Goldberg, Perlis and Bowden 9 , Reference Benazzi 17 – Reference Koukopoulos and Sani 19

Moreover, compared with non-mixed depression, mixed depression is more common in BD than in unipolar depression, and it is more frequently associated with a family history of BD,Reference Perugi, Quaranta and Dell’Osso 20 younger age at onset,Reference Goldberg, Perlis and Bowden 9 , Reference Swann, Suppes and Ostacher 21 , Reference Angst, Cui and Swendsen 22 longer duration,Reference Bottlender, Sato, Kleindienst, Strauss and Möller 25 , Reference Sato, Bottlender, Schröter and Möller 26 worse outcome,Reference Swann, Suppes and Ostacher 21 , Reference Goldberg 27 , Reference Koukopoulos, Albert, Sani, Koukopoulos and Girardi 28 and poorer response to treatment.Reference Benazzi 18 , Reference Balázs, Benazzi, Rihmer, Rihmer, Akiskal and Akiskal 29 – Reference Dell’Osso, Dobrea and Cremaschi 31

Clinical Characteristics

Patients with BD who present with manic/hypomanic or depressive episodes with mixed features are associated with more severe forms of BD along with a worse course of illness and higher rates of comorbid conditions.Reference Grande, Berk, Birmaher and Vieta 30 , Reference Dell’Osso, Dobrea and Cremaschi 31 Most studies report that mixed mania as well as mixed depression start at a younger age than purely affective events,Reference Goldberg, Perlis and Bowden 9 , Reference Perugi and Akiskal 11 , Reference Benazzi 17 , Reference Cassidy and Carroll 32 – Reference Valenti, Pacchiarotti and Rosa 34 although other studies have reported a similar or older age of onset.Reference Perugi and Akiskal 11 , Reference Benazzi 18 , Reference Hantouche, Akiskal, Azorin, Châtenet-Duchêne and Lancrenon 35 When compared to patients affected by pure manic episodes, mixed-mania patients tend to experience more episodes of illness, with longer durationsReference Martin-Carrasco, Gonzalez-Pinto, Galan, Ballesteros, Maurino and Vieta 36 and increased impairment.Reference Rosa, Reinares and Franco 37 In addition, patients with a previous mixed episode are more likely to show shorter interepisode intervals, higher rates of suicide attempts, and higher comorbidity with substance misuse (specially alcohol abuse in mixed depression)Reference Cassidy, Yatham, Berk and Grof 14 , Reference Benazzi 17 , Reference González-Pinto, Aldama, Mosquera and González Gómez 33 , Reference Valenti, Pacchiarotti and Rosa 34 than non-mixed patients.

The new quantitative DSM–5 classification of BD with mixed features (see Tables 1 and 2) and BD without mixed features (manic/hypomanic with three to six mixed features or depressed with three to seven mixed features) may be helpful for statistical measurements, quantification of illness severity, and stratified analyses investigating changes between mood disorder categories or severity levels.Reference Vieta and Valentí 1 However, the list of symptoms proposed in this DSM–5 specifier has been widely criticized. The DSM–5 specifier includes typical manic symptoms (such as elevated mood and grandiosity) that are rare among patients with mixed depression, while excluding symptoms (such as irritability, psychomotor agitation, and distractibility) that are frequently reported in this patient population.Reference Koukopoulos and Sani 19 , Reference Malhi and Geddes 38 , Reference Matza, Rajagopalan, Thompson and de Lissovoy 39

Table 1 Description of the old (DSM–IV–TR) classification criteria for mood episodes

BDNOS=bipolar disorder not otherwise specified.

Adapted from Vieta & Valentí, 2013.Reference Vieta and Valentí 1

Table 2 Description of the new (DSM–5) classification criteria for mood episodes

Adapted from Vieta & Valentí, 2013.Reference Vieta and Valentí 1

Moreover, the inclusion of biomarkers for the diagnosis of BD was a goal to which the planners of the DSM–5 aspired, but their absence has not made it possible.Reference Vieta 42 , Reference He, Xu and Sun 43 Despite this, precision psychiatry is currently postulated as a valid formulation for an accurate diagnosis and a better treatment approach.Reference Perugi, Angst and Azorin 44

Manic episodes with mixed features, compared to episodes without mixed symptomatology, present with greater emotional lability and irritability, less euphoria, prolonged emotional instability, less involvement in pleasurable activities, less knowledge of grandiosity, and less of a decreased need for sleep.Reference Perugi and Akiskal 11 Dysphoric mood, anxiety, excessive guilt, and suicidal depressive symptoms are also common.Reference Cassidy, Yatham, Berk and Grof 14 , Reference Perugi, Quaranta and Dell’Osso 20 , Reference Swann, Suppes and Ostacher 21

Not all patients develop a typical mixed presentation, often without manic and/or depressive features being the most dominant symptoms.Reference Kupfer, First and Regier 40 , Reference He, Xu and Sun 43 In the presence of psychotic features, perceptual and motor impairment, or negative symptoms, an association with manic and depressive episodes may be difficult as the patient can be misdiagnosed with schizophrenia and other related psychoses.Reference Benazzi 17 , Reference Perugi, Angst and Azorin 44

As far as mixed symptoms in depression are concerned, several studies report irritability, emotional liability, increased cognitive activity (distractibility, tachypsychia), and psychomotor hyperactivity (restlessness, impulsivity, and increased talkativeness) as core symptoms.Reference Goldberg, Perlis and Bowden 9 , Reference Akiskal, Akiskal and Lancrenon 16 , Reference Perugi, Quaranta and Dell’Osso 20 , Reference Sato, Bottlender, Schröter and Möller 26 In addition, these symptoms are generally experienced with much distress for the patient, leading to increased risk of suicidality.Reference Koukopoulos, Albert, Sani, Koukopoulos and Girardi 28 , Reference Pacchiarotti, Mazzarini and Kotzalidis 45

Comparing mixed depression with agitated depression, the common factors are: irritability/aggressiveness, flights of ideas, racing thoughts, psychomotor agitation, increased talkativeness, and distractibility.Reference Swann, Suppes and Ostacher 21 , Reference Maj, Pirozzi, Magliano, Fiorillo and Bartoli 23 For this reason, since the DSM–III, psychomotor agitation has been included as a subcriterion for the diagnosis of both manic episodes and MDEs. Additionally, psychomotor agitation has also been considered an overlapping affective symptom, which resulted in its exclusion, together with irritability and distractibility, as a criterion for an MDE with mixed features in the new DSM–5 proposal.Reference Vieta and Valentí 1 In addition, psychomotor agitation in major depression disorder (MDD) has been proposed as an indicator of mood switching in 8.18% of medicated patients with unipolar depression.Reference Baldessarini, Faedda and Offidani 46 – Reference Bowden 49

This risk may be higher in patients with clinical features of psychosis or mental retardation, a history of depressive recurrences, a family history of mood disorders, prior antidepressant treatment, and earlier age of onset.Reference Angst, Cui and Swendsen 22 , Reference Goldberg 27 , Reference Pacchiarotti, Nivoli and Mazzarini 51 Other studies have shown that MDD patients with agitation are nearly threefold as likely to experience mood switches, suggesting that psychomotor agitation in MDD may be related to an indicator of BD.Reference Goldberg 27 , Reference Carroll 41 For this reason, patients with bipolar depression medicated with antidepressants should be monitored in order to detect signs of mixed depression,Reference Sani, Napoletano and Vöhringer 53 probably represented by psychomotor activation or inhibition and irritability.Reference Vieta and Valentí 1 , Reference Perugi and Akiskal 11 , Reference Swann, Suppes and Ostacher 21 , Reference Judd, Schettler and Akiskal 24

Mixed Features in Bipolar Disorders and Suicidality

Among mental disorders, bipolar disorder is one of the main causes of suicidal behavior.Reference Swann, Suppes and Ostacher 21 , Reference Bottlender, Sato, Kleindienst, Strauss and Möller 25 Estimated rates of death by suicide among people with BD are 0.2–0.4 per 100 person-years, while rates of suicide attempts rise to half of patients with BD throughout their lives, and about 15–20% of attempts are successful.Reference Grande, Berk, Birmaher and Vieta 30 Compared to patients with MDD, suicide attempts in patients with BD tend to be more lethal, especially among men. Therefore, all suicidality in BD patients should be considered to have a high potential for lethality.Reference Seo, Wang, Jun, Woo and Bahk 52

Several studies have reported an association between suicidal behavior in BD patients and more episodes of major depression, mixed states, rapid cycling,Reference Seo, Wang, Jun, Woo and Bahk 52 younger age at onset, concurrent substance abuse disorder, family history of suicide attempts, and comorbid anxiety disorders.Reference Undurraga, Baldessarini and Valentí 2 , Reference Sani, Napoletano and Vöhringer 53 , Reference Reinares, Bonnín and Hidalgo-Mazzei 54 In particular, bipolar patients with mixed states have been shown to have a higher risk of suicide than those with non-mixed states.Reference Meier, Petersen, Mattheisen, Mors, Mortensen and Laursen 55 Some current studies show that mixed features found at the index episode, defined by the DSM–5, are probably the most important risk factor for suicidal behavior in this population.Reference Seo, Wang, Jun, Woo and Bahk 52 Other authors found that the association between suicidality and mixed mania and mixed depression is a predictor of future suicidal acts.Reference Sani, Napoletano and Vöhringer 53 Compared with patients affected by pure mania, patients suffering from mixed states not only show more frequent suicidal ideation but also reported a longer time to recovery and were more likely to relapse. In addition, they face greater difficulties in responding to mood stabilizers.Reference González-Pinto, Aldama, Mosquera and González Gómez 33 Moreover, the presence of psychomotor agitation and racing thoughts during mixed depression has been found to be associated with a higher risk of suicidal ideation.Reference Balázs, Benazzi, Rihmer, Rihmer, Akiskal and Akiskal 29 , Reference Pacchiarotti, Mazzarini and Kotzalidis 45 , Reference Popovic, Vieta and Azorin 56

Considering DSM–5 classification, mixed depressive episodes are three times more common in BD type II compared with unipolar depression, and they partly contribute to the increased risk of suicide observed in BD type II compared to unipolar depression.Reference Dell’Osso, Dobrea and Cremaschi 31 , Reference Benazzi 17 In this regard, it has been proposed that the DSM–5 “mixed state” definition and characteristics are more sensitive than the DSM–IV criteria when it comes to predicting suicidal tendencies.57

Conclusions

In recent years, the diagnostic definitions of mixed states in BD patients have experienced an important evolution from categorical diagnostic criteria (DSM–IV–TR) to dimensional criteria (DSM–5). The nosological definition of mixed features is crucial for a reliable and valid diagnosis that enhances clinical decision making. Hence, mixed states are common in BD,Reference Akiskal, Bourgeois, Angst, Post, Möller and Hirschfeld 13 but the existence of different definitions affects the measure of their prevalence across different studies.

It is now clear that the DSM–IV–TR criteria for mixed states in BD were too narrow, and many patients who met those clinical criteria were excluded from the definition of mixed states and were finally diagnosed with “BD unspecified.”Reference Vieta, Grunze, Azorin and Fagiolini 57 In the DSM–5, although inclusion of the symptoms of mixed features has been criticized because of the main symptomatology, it seems that the specific diagnostic category may be more likely to improve increased diagnostic sensitivity with earlier identification of symptoms—for instance, risky behavior, psychomotor agitation, and impulsivity in patients with MDE—to ensure specific treatment and improve relapse prevention, and it could represent an important step toward suicide prevention.

Disclosures

Eva Solé and Marina Garriga hereby state that they have no conflicts of interest to declare. Marc Valentí has received research grants from Eli Lilly & Company and has served as a speaker for Abbott, Bristol–Myers Squibb, GlaxoSmithKline, Jansen–Cilag, and Lundbeck. Eduard Vieta has received grants and served as a consultant, advisor, and CME speaker for the following entities: AB–Biotics, Actavis, Allergan, AstraZeneca, Bristol–Myers Squibb, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi–Aventis, Servier, Shire, Sunovion, Takeda, Telefónica, the Brain & Behavior Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), and the Stanley Medical Research Institute.

Footnotes

The authors are grateful for the support of CIBERSAM, the Spanish Ministry of Economy and Competitiveness (PI 12/00910); the Plan Nacional de I+D+I y cofinanciado por el ISCIII Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional; and the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya for the Bipolar Disorders Group (2014 SGR 398).

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Figure 0

Table 1 Description of the old (DSM–IV–TR) classification criteria for mood episodes

Figure 1

Table 2 Description of the new (DSM–5) classification criteria for mood episodes