Skip to main content Accessibility help
×
×
Home

Information:

  • Access
  • Cited by 11
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Suppes, Trisha Eberhard, Jonas Lemming, Ole Young, Allan H. and McIntyre, Roger S. 2017. Anxiety, irritability, and agitation as indicators of bipolar mania with depressive symptoms: a post hoc analysis of two clinical trials. International Journal of Bipolar Disorders, Vol. 5, Issue. 1,

    Verdolini, N. Perugi, G. Samalin, L. Murru, A. Angst, J. Azorin, J.-M. Bowden, C. L. Mosolov, S. Young, A. H. Barbuti, M. Guiso, G. Popovic, D. Vieta, E. and Pacchiarotti, I. 2017. Aggressiveness in depression: a neglected symptom possibly associated with bipolarity and mixed features. Acta Psychiatrica Scandinavica, Vol. 136, Issue. 4, p. 362.

    Vieta, Eduard and Montes, José Manuel 2018. A Review of Asenapine in the Treatment of Bipolar Disorder. Clinical Drug Investigation, Vol. 38, Issue. 2, p. 87.

    Vieta, Edouardo and Bourgeois, Marc L. 2018. Andrés Piquer (1711–1772) et sa contribution à la conceptualisation du trouble bipolaire maniaco-dépressif. Annales Médico-psychologiques, revue psychiatrique, Vol. 176, Issue. 6, p. 627.

    Malhi, Gin S Irwin, Lauren Hamilton, Amber Morris, Grace Boyce, Philip Mulder, Roger and Porter, Richard J 2018. Modelling mood disorders: An ACE solution?. Bipolar Disorders, Vol. 20, Issue. , p. 4.

    Vieta, Eduard Montes, José Manuel Iborra, Pedro Mozos, Alfonso Sáez, Cristina and Benabarre, Antonio 2018. Uso de asenapina en la práctica clínica: recomendaciones de un panel de expertos. Revista de Psiquiatría y Salud Mental,

    Verdolini, N. Hidalgo-Mazzei, D. Murru, A. Pacchiarotti, I. Samalin, L. Young, A. H. Vieta, E. and Carvalho, A. F. 2018. Mixed states in bipolar and major depressive disorders: systematic review and quality appraisal of guidelines. Acta Psychiatrica Scandinavica, Vol. 138, Issue. 3, p. 196.

    Vázquez, Gustavo H. Lolich, María Cabrera, Casimiro Jokic, Ruzica Kolar, Dusan Tondo, Leonardo and Baldessarini, Ross J. 2018. Mixed symptoms in major depressive and bipolar disorders: A systematic review. Journal of Affective Disorders, Vol. 225, Issue. , p. 756.

    Vieta, Eduard Berk, Michael Schulze, Thomas G. Carvalho, André F. Suppes, Trisha Calabrese, Joseph R. Gao, Keming Miskowiak, Kamilla W. and Grande, Iria 2018. Bipolar disorders. Nature Reviews Disease Primers, Vol. 4, Issue. , p. 18008.

    Tondo, L. Vázquez, G. H. Pinna, M. Vaccotto, P. A. and Baldessarini, R. J. 2018. Characteristics of depressive and bipolar disorder patients with mixed features. Acta Psychiatrica Scandinavica, Vol. 138, Issue. 3, p. 243.

    Vieta, Eduard 2019. Bipolar II Disorder. p. 278.

    ×

Actions:

      • Send article to Kindle

        To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Mixed features in bipolar disorder
        Available formats
        ×

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Mixed features in bipolar disorder
        Available formats
        ×

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Mixed features in bipolar disorder
        Available formats
        ×
Export citation

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.

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).

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. 1 , 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. 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. 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. 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. 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. 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, 9 , 10 even though such other symptoms as severe anxiety, prolonged emotional instability, psychotic experiences, and disorganized behavior may be frequent. 11 This is a recognized problem that has been considered to be associated with a loss of diagnostic validity. 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.” 8

Epidemiology

Mixed states are common in BD, 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. 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. 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, 15 17 some prevalence studies report a higher rate among women (63–69%). 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. 9 , 17 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, 20 younger age at onset, 9 , 21 , 22 longer duration, 25 , 26 worse outcome, 21 , 27 , 28 and poorer response to treatment. 18 , 29 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. 30 , 31 Most studies report that mixed mania as well as mixed depression start at a younger age than purely affective events, 9 , 11 , 17 , 32 34 although other studies have reported a similar or older age of onset. 11 , 18 , 35 When compared to patients affected by pure manic episodes, mixed-mania patients tend to experience more episodes of illness, with longer durations 36 and increased impairment. 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) 14 , 17 , 33 , 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. 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. 19 , 38 , 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. 1

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

Adapted from Vieta & Valentí, 2013. 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. 42 , 43 Despite this, precision psychiatry is currently postulated as a valid formulation for an accurate diagnosis and a better treatment approach. 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. 11 Dysphoric mood, anxiety, excessive guilt, and suicidal depressive symptoms are also common. 14 , 20 , 21

Not all patients develop a typical mixed presentation, often without manic and/or depressive features being the most dominant symptoms. 40 , 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. 17 , 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. 9 , 16 , 20 , 26 In addition, these symptoms are generally experienced with much distress for the patient, leading to increased risk of suicidality. 28 , 45

Comparing mixed depression with agitated depression, the common factors are: irritability/aggressiveness, flights of ideas, racing thoughts, psychomotor agitation, increased talkativeness, and distractibility. 21 , 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. 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. 46 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. 22 , 27 , 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. 27 , 41 For this reason, patients with bipolar depression medicated with antidepressants should be monitored in order to detect signs of mixed depression, 53 probably represented by psychomotor activation or inhibition and irritability. 1 , 11 , 21 , 24

Mixed Features in Bipolar Disorders and Suicidality

Among mental disorders, bipolar disorder is one of the main causes of suicidal behavior. 21 , 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. 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. 52

Several studies have reported an association between suicidal behavior in BD patients and more episodes of major depression, mixed states, rapid cycling, 52 younger age at onset, concurrent substance abuse disorder, family history of suicide attempts, and comorbid anxiety disorders. 2 , 53 , 54 In particular, bipolar patients with mixed states have been shown to have a higher risk of suicide than those with non-mixed states. 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. 52 Other authors found that the association between suicidality and mixed mania and mixed depression is a predictor of future suicidal acts. 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. 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. 29 , 45 , 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. 31 , 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, 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.” 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.

References

1. Vieta, E, Valentí, M. Mixed states in the DSM–5: implications for clinical care, education, and research. J Affect Disord. 2013; 148(1): 2836. Epub ahead of print Apr 2. http://www.jad-journal.com/article/S0165-0327(13)00232-2/pdf.
2. Undurraga, J, Baldessarini, RJ, Valentí, M, et al. Bipolar depression: clinical correlates of receiving antidepressants. J Affect Disord. 2012; 139(1): 8993. Epub ahead of print Mar 9.
3. Shim, IH, Woo, YS, Bahk, WM. Prevalence rates and clinical implications of bipolar disorder “with mixed features” as defined by the DSM–5. J Affect Disord. 2015; 173: 120125.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision. Washington, DC: American Psychiatric Association; 2000.
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
6. Marneros, A, Goodwin, F, eds. Bipolar Disorders: Mixed States, Rapid Cycling and Atypical Forms. Cambridge: Cambridge University Press; 2005.
7. Wittchen, HU, Höfler, M, Gloster, AT, Craske, MG, Beesdo, K. 2011. Options and dilemmas of dimensional measures for the DSM–5: which types of measures fare best in predicting course and outcome. In: Regier DA, Narrow WE, Kuhl EA, Kupfer DJ, eds. Options and Dilemmas of Dimensional Measures for DSM–5: Which Types of Measures Fare Best in Predicting Course and Outcome. Arlington, VA: American Psychiatric Publishing; 2011: 119146.
8. 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: 173181. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2008.08050746.
9. Swann, AC, Moeller, FG, Steinberg, JL, Schneider, L, Barratt, ES, Dougherty, DM. Manic symptoms and impulsivity during bipolar depressive episodes. Bipolar Disord. 2007; 9(3): 206212. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723749/pdf/nihms128564.pdf.
10. Perugi, G, Akiskal, HS. Emerging concepts of mixed states: a longitudinal perspective. In: Marneros A., Goodwin FK, eds. Emerging Concepts of Mixed States: A Longitudinal Perspective. Cambridge: Cambridge University Press; 2005: 4560.
11. Lecrubier, Y. Refinement of diagnosis and disease classification in psychiatry. Eur Arch Psychiatry Clin Neurosci. 2008; 258(Suppl 1): 611.
12. Akiskal, HS, Bourgeois, ML, Angst, J, Post, R, Möller, H, Hirschfeld, R. Reevaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord. 2000; 59(Suppl 1): S5S30.
13. Cassidy, F, Yatham, LN, Berk, M, Grof, P. Pure and mixed manic subtypes: a review of diagnostic classification and validation. Bipolar Disord. 2008; 10: 131143.
14. Benazzi, F. The role of gender in depressive mixed state. Psychopathology. 2003; 36: 213217.
15. Akiskal, HS, Akiskal, KK, Lancrenon, S, et al. Validating the bipolar spectrum in the French National EPIDEP Study: overview of the phenomenology and relative prevalence of its clinical prototypes. J Affect Disord. 2006; 96(3): 197205. Epub ahead of print Jul 7.
16. Azorin, JM, Kaladjian, A, Adida, M, et al. Self-assessment and characteristics of mixed depression in the French national EPIDEP study. J Affect Disord. 2012; 143(1–3): 109117. Epub ahead of print Jul 30.
17. Benazzi, F. Reviewing the diagnostic validity and utility of mixed depression (depressive mixed states). Eur Psychiatry. 2008; 23: 4048. Epub ahead of print Aug 30, 2007.
18. Koukopoulos, a., Sani, G. DSM–5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014; 129(1): 416. Epub ahead of print Apr 19, 2013.
19. Perugi, G, Quaranta, G, Dell’Osso, L. The significance of mixed states in depression and mania. Curr Psychiatry Rep. 2014; 16(10): 486.
20. Swann, AC, Suppes, T, Ostacher, MJ, et al. Multivariate analysis of bipolar mania: retrospectively assessed structure of bipolar I manic and mixed episodes in randomized clinical trial participants. J Affect Disord. 2013; 144(1–2): 5964. Epub ahead of print Aug 1, 2012.
21. Angst, J, Cui, L, Swendsen, J, et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry. 2010; 167(10): 11941201. Epub ahead of print Aug 16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145248/pdf/nihms249007.pdf.
22. Maj, M, Pirozzi, R, Magliano, L, Fiorillo, A, Bartoli, L. Agitated “unipolar” major depression: prevalence, phenomenology, and outcome. J Clin Psychiatry. 2006; 67(5): 712719.
23. Judd, LL, Schettler, PJ, Akiskal, HS, et al. Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes. J Affect Disord. 2012; 138(3): 440448. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677770/pdf/nihms468685.pdf.
24. Bottlender, T, Sato, T, Kleindienst, N, Strauss, A, Möller, HJ. Mixed depressive features predict maniform switch during treatment of depression in bipolar I disorder. J Affect Disord. 2004; 78(2): 149152.
25. Sato, T, Bottlender, R, Schröter, A, Möller, HJ. Frequency of manic symptoms during a depressive episode and unipolar “depressive mixed state” as bipolar spectrum. Acta Psychiatr Scand. 2003; 107(4): 268274.
26. Goldberg, JF. Differential diagnosis of bipolar disorder. CNS Spectr. 2010; 15(2 Suppl 3): 47; discussion 17.
27. Koukopoulos, A, Albert, MJ, Sani, G, Koukopoulos, AE, Girardi, P. Mixed depressive states: nosologic and therapeutic issues. Int Rev Psychiatry. 2005; 17(1): 2137.
28. Balázs, J, Benazzi, F, Rihmer, Z, Rihmer, A, Akiskal, KK, Akiskal, HS. The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention. J Affect Disord. 2006; 91(2–3): 133138.
29. Grande, I, Berk, M, Birmaher, B, Vieta, E. Bipolar disorder. Lancet. 2016; 387(10027): 15611572. Epub ahead of print Sep 18.
30. Dell’Osso, B, Dobrea, C, Cremaschi, L, et al. Italian bipolar II vs. I patients have better individual functioning, in spite of overall similar illness severity. CNS Spectr. 2016; 24: 18.
31. Cassidy, F, Carroll, BJ. The clinical epidemiology of pure and mixed manic episodes. Bipolar Disord. 2001; 3(1): 3540.
32. González-Pinto, A, Aldama, A, Mosquera, F, González Gómez, C. Epidemiology, diagnosis and management of mixed mania. CNS Drugs. 2007; 21(8): 611626.
33. Valenti, M, Pacchiarotti, I, Rosa, AR, et al. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients. Bipolar Disord. 2011; 13(2): 145154.
34. Hantouche, EG, Akiskal, HS, Azorin, JM, Châtenet-Duchêne, L, Lancrenon, S. Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients. J Affect Disord. 2006; 96(3): 225232.
35. Martin-Carrasco, M, Gonzalez-Pinto, A, Galan, JL, Ballesteros, J, Maurino, J, Vieta, E. Number of prior episodes and the presence of depressive symptoms are associated with longer length of stay for patients with acute manic episodes. Ann Gen Psychiatry. 2012; 11(1): 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312846/pdf/1744-859X-11-7.pdf.
36. Rosa, AR, Reinares, M, Franco, C, et al. Clinical predictors of functional outcome of bipolar patients in remission. Bipolar Disord. 2009; 11(4): 401409.
37. Malhi, GS, Geddes, JR. Carving bipolarity using a lithium sword. Br J Psychiatry. 2014; 205(5): 337339. http://bjp.rcpsych.org/content/205/5/337.long.
38. Matza, LS, Rajagopalan, KS, Thompson, CL, de Lissovoy, G. Misdiagnosed patients with bipolar disorder: comorbidities, treatment patterns, and direct treatment costs. J Clin Psychiatry. 2005; 66(11): 14321440.
39. Kupfer, D, First, M, Regier, D. A Research Agenda for the DSM–V. Arlington, VA: American Psychiatric Association; 2002.
40. Carroll, BJ. Biomarkers in DSM–5: lost in translation. Aust N Z J Psychiatry. 2013; 47(7): 676678.
41. Vieta, E. Personalised medicine applied to mental health: precision psychiatry [in Spanish]. Rev Psiquiatr y Salud Ment. 2015; 8(3): 117118. Epub ahead of print May 8. http://www.elsevier.es/es-revista-revista-psiquiatria-salud-mental-286-linkresolver-la-medicina-personalizada-aplicada-salud-S1888989115000907.
42. He, H, Xu, G, Sun, B, et al. The use of 15-point hypomanic checklist in differentiating bipolar I and bipolar II disorder from major depressive disorder. Gen Hosp Psychiatry. 2014; 36(3): 347351. Epub ahead of print Dec 25, 2013.
43. Perugi, G, Angst, J, Azorin, JM, et al. Relationships between mixed features and borderline personality disorder in 2811 patients with major depressive episode. Acta Psychiatr Scand. 2015; 111. Epub ahead of print.
44. Pacchiarotti, I, Mazzarini, L, Kotzalidis, GD, et al. Mania and depression: mixed, not stirred. J Affect Disord. 2011; 133(1–2): 105113. Epub ahead of print Apr 22.
45. Baldessarini, RJ, Faedda, GL, Offidani, E, et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review. J Affect Disord. 2012; 148(1): 129135. Epub ahead of print Dec 6.
46. Himmelhoch, JM, Mulla, D, Neil, JF, Detre, TP, Kupfer, DJ. Incidence and significance of mixed affective states in a bipolar population. Arch Gen Psychiatry. 1976; 33(9): 10621066.
47. Garriga, M, Pacchiarotti, I, Kasper, S, et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry. 2016; 17(2): 86128.
48. Bowden, CL. Comorbidities with bipolar disorders: significance, recognition, and management. CNS Spectr. 2010; 15(2 Suppl 3): 89; discussion 17.
49. Pacchiarotti, I, Nivoli, AM, Mazzarini, L, et al. The symptom structure of bipolar acute episodes: in search for the mixing link. J Affect Disord. 2013; 149(1–3): 5666. Epub ahead of print Feb 7.
50. Seo, HJ, Wang, HR, Jun, TY, Woo, YS, Bahk, WM. Factors related to suicidal behavior in patients with bipolar disorder: the effect of mixed features on suicidality. Gen Hosp Psychiatry. 2016; 39: 9196.
51. Sani, G, Napoletano, F, Vöhringer, PA, et al. Mixed depression: clinical features and predictors of its onset associated with antidepressant use. Psychother Psychosom. 2014; 83: 213221.
52. Reinares, M, Bonnín, C del M, Hidalgo-Mazzei, D, et al. Making sense of DSM–5 mania with depressive features. Aust N Z J Psychiatry. 2015; 49(6): 540549.
53. Meier, SM, Petersen, L, Mattheisen, M, Mors, O, Mortensen, PB, Laursen, TM. Secondary depression in severe anxiety disorders: a population-based cohort study in Denmark. Lancet Psychiatry. 2015; 2(6): 515523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087327/pdf/nihms824338.pdf.
54. Popovic, D, Vieta, E, Azorin, JM, et al. Suicide attempts in major depressive episode: evidence from the BRIDGE–II–Mix study. Bipolar Disord. 2015; 17(7): 795803. Epub ahead of print Sep 29.
55. Vieta, E, Grunze, H, Azorin, JM, Fagiolini, A. Phenomenology of manic episodes according to the presence or absence of depressive features as defined in the DSM–5: results from the IMPACT self-reported online survey. J Affect Disord. 2014; 156: 206213. Epub ahead of print Jan 1. http://www.jad-journal.com/article/S0165-0327(13)00884-7/pdf.