Prevalence rates and clinical implications of bipolar disorder “with mixed features” as defined by DSM-5

Mood episodes with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)–defined mixed features are highly prevalent in bipolar disorder (BD), affecting ~40% of patients during the course of illness. Mixed states are associated with poorer clinical outcomes, greater treatment resistance, higher rates of comorbidity, more frequent mood episodes, and increased rates of suicide. The objectives of the current review are to identify, summarize, and synthesize studies assessing the efficacy of treatments specifically for BD I and II mood episodes (ie, including manic, hypomanic, and major depressive episodes) with DSM-5–defined mixed features. Two randomized controlled trials (RCTs) and 6 post-hoc analyses were identified, all of which assessed the efficacy of second-generation antipsychotics (SGAs) for the acute treatment of BD mood episodes with mixed features. Results from these studies provide preliminary support for SGAs as efficacious treatments for both mania with mixed features and bipolar depression with mixed features. However, there are inadequate data to definitively support or refute the clinical use of specific agents. Conventional mood stabilizing agents (eg, lithium and divalproex) have yet to have been adequately studied in DSM-5–defined mixed features. Further study is required to assess the efficacy, safety, and tolerability of treatments specifically for BD mood episodes with mixed features.

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Clinical correlates of DSM-5 mixed features in bipolar disorder: A meta-analysis

Journal of Affective Disorders ◽

10.1016/j.jad.2020.07.035 ◽

2020 ◽

Vol 276 ◽

pp. 234-240

Author(s):

Francesco Bartoli ◽

Cristina Crocamo ◽

Giuseppe Carrà

Keyword(s):

Bipolar Disorder ◽

Meta Analysis ◽

Clinical Correlates ◽

Dsm 5 ◽

Mixed Features

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DSM-5-defined ‘mixed features’ and Benazzi's mixed depression: Which is practically useful to discriminate bipolar disorder from unipolar depression in patients with depression?

Psychiatry and Clinical Neurosciences ◽

10.1111/pcn.12213 ◽

2014 ◽

Vol 69 (2) ◽

pp. 109-116 ◽

Cited By ~ 25

Author(s):

Minoru Takeshima ◽

Takashi Oka

Keyword(s):

Bipolar Disorder ◽

Unipolar Depression ◽

Dsm 5 ◽

Mixed Features

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Factors related to suicidal behavior in korean patients with bipolar disorder: The effect of mixed features on suicidality

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.710 ◽

2016 ◽

Vol 33 (S1) ◽

pp. s270-s271

Author(s):

H.J. Seo ◽

H.R. Wang ◽

Y.S. Woo ◽

H.C. Kim ◽

W.M. Bahk ◽

...

Keyword(s):

Risk Factors ◽

Bipolar Disorder ◽

Suicidal Behavior ◽

Significant Risk ◽

Suicidal Behaviors ◽

Korean Patients ◽

Dsm 5 ◽

Mixed Features ◽

Bipolar Patients ◽

Depressive Episodes

IntroductionThe aim of the present study was to investigate various risk factors of suicidal behaviors, including the mixed features specifier, in Korean patients with bipolar disorder.MethodsWe retrospectively reviewed medical charts from 2005 to 2014. A total of 334 patients diagnosed with bipolar disorder using the DSM-IV TR were enrolled. Subjects were categorized into two groups according to their history of suicidal behavior and the demographic and clinical characteristics of the groups were compared, including the mixed features specifier. We re-evaluated the index episode using DSM-5 criteria and classified subjects into an index episode with mixed features group and an index episode without mixed features group. Logistic regression was performed to evaluate significant risk factors associated with suicidal behavior.ResultsSuicidal behavior had an independent relationship with mixed features at the index episode using DSM-5 criteria (OR = 3.39; 95% CI: 1.57–7.34) and number of previous depressive episodes (OR = 1.62; 95% CI: 1.34–1.95) in Korean bipolar patients. The mixed feature specifier was the strongest risk factor for suicidal behavior in the present study. Limitations: this was a retrospective study and structured psychiatric interviews were not conducted.ConclusionsThis study may help clinicians understand potential risk factors and manage bipolar disorders with suicidal behaviors. Clinicians should carefully monitor patients with bipolar disorder who exhibit numerous depressive episodes or mixed features for suicidal behavior.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Mixed features in bipolar disorder

CNS Spectrums ◽

10.1017/s1092852916000869 ◽

2016 ◽

Vol 22 (2) ◽

pp. 134-140 ◽

Cited By ~ 26

Author(s):

Eva Solé ◽

Marina Garriga ◽

Marc Valentí ◽

Eduard Vieta

Keyword(s):

Bipolar Disorder ◽

Diagnostic Category ◽

Specific Treatment ◽

Unipolar Depression ◽

Manic Symptoms ◽

Dsm 5 ◽

Increased Risk ◽

Mixed Features ◽

Major Depressive Episodes ◽

Depressive Episodes

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.

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Not Only Mania or Depression: Mixed States/Mixed Features in Paediatric Bipolar Disorders

Brain Sciences ◽

10.3390/brainsci11040434 ◽

2021 ◽

Vol 11 (4) ◽

pp. 434

Author(s):

Delfina Janiri ◽

Eliana Conte ◽

Ilaria De Luca ◽

Maria Velia Simone ◽

Lorenzo Moccia ◽

...

Keyword(s):

Systematic Review ◽

Bipolar Disorders ◽

Prevalence Rates ◽

Mixed States ◽

Total Patient ◽

Hyperactivity Disorder ◽

Mixed Features ◽

Paediatric Age ◽

Meta Analyses ◽

The Relationship

Background: early onset is frequent in Bipolar Disorders (BDs), and it is characterised by the occurrence of mixed states (or mixed features). In this systematic review, we aimed to confirm and extend these observations by providing the prevalence rates of mixed states/features and data on associated clinical, pharmacological and psychopathological features. Methods: following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched from inception to 9 February 2021 for all studies investigating mixed states/mixed features in paediatric BD. Data were independently extracted by multiple observers. The prevalence rates of mixed states/features for each study were calculated. Results: eleven studies were included in our review, involving a total patient population of 1365 individuals. Overall, of the patients with paediatric age BD, 55.2% had mixed states/features (95% CI 40.1–70.3). Children with mixed states/features presented with high rates of comorbidities, in particular, with Attention Deficit Hyperactivity Disorder (ADHD). Evidences regarding the psychopathology and treatment response of mixed states/features are currently insufficient. Conclusions: our findings suggested that mixed states/features are extremely frequent in children and adolescents with BD and are characterised by high levels of comorbidity. Future investigations should focus on the relationship between mixed states/features and psychopathological dimensions as well as on the response to pharmacological treatment.

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Measures of the DSM–5 mixed-features specifier of major depressive disorder

CNS Spectrums ◽

10.1017/s1092852916000857 ◽

2017 ◽

Vol 22 (2) ◽

pp. 196-202 ◽

Cited By ~ 4

Author(s):

Mark Zimmerman

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Antidepressant Medication ◽

Reliability And Validity ◽

Mixed States ◽

Major Depressive ◽

Manic Symptoms ◽

Dsm 5 ◽

Depressed Patients ◽

Mixed Features

During the past two decades, a number of studies have found that depressed patients frequently have manic symptoms intermixed with depressive symptoms. While the frequency of mixed syndromes are more common in bipolar than in unipolar depressives, mixed states are also common in patients with major depressive disorder. The admixture of symptoms may be evident when depressed patients present for treatment, or they may emerge during ongoing treatment. In some patients, treatment with antidepressant medication might precipitate the emergence of mixed states. It would therefore be useful to systematically inquire into the presence of manic/hypomanic symptoms in depressed patients. We can anticipate that increased attention will likely be given to mixed depression because of changes in the DSM–5. In the present article, I review instruments that have been utilized to assess the presence and severity of manic symptoms and therefore could be potentially used to identify the DSM–5 mixed-features specifier in depressed patients and to evaluate the course and outcome of treatment. In choosing which measure to use, clinicians and researchers should consider whether the measure assesses both depression and mania/hypomania, assesses all or only some of the DSM–5 criteria for the mixed-features specifier, or assesses manic/hypomanic symptoms that are not part of the DSM–5 definition. Feasibility, more so than reliability and validity, will likely determine whether these measures are incorporated into routine clinical practice.

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The "selfish brain" hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia

Trends in Psychiatry and Psychotherapy ◽

10.1590/s2237-60892012000300003 ◽

2012 ◽

Vol 34 (3) ◽

pp. 121-128 ◽

Cited By ~ 8

Author(s):

Rodrigo Barbachan Mansur ◽

Elisa Brietzke

Keyword(s):

Bipolar Disorder ◽

Energy Metabolism ◽

Energy Supply ◽

Clinical Implications ◽

Metabolic Abnormalities ◽

Compensatory Mechanisms ◽

High Prevalence ◽

Brain Theory ◽

The Brain ◽

Brain Energy

Metabolic abnormalities are frequent in patients with schizophrenia and bipolar disorder (BD), leading to a high prevalence of diabetes and metabolic syndrome in this population. Moreover, mortality rates among patients are higher than in the general population, especially due to cardiovascular diseases. Several neurobiological systems involved in energy metabolism have been shown to be altered in both illnesses; however, the cause of metabolic abnormalities and how they relate to schizophrenia and BD pathophysiology are still largely unknown. The "selfish brain" theory is a recent paradigm postulating that, in order to maintain its own energy supply stable, the brain modulates energy metabolism in the periphery by regulation of both allocation and intake of nutrients. We hypothesize that the metabolic alterations observed in these disorders are a result of an inefficient regulation of the brain energy supply and its compensatory mechanisms. The selfish brain theory can also expand our understanding of stress adaptation and neuroprogression in schizophrenia and BD, and, overall, can have important clinical implications for both illnesses.

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Rethinking the spectrum of mood disorders: implications for diagnosis and management – Proceedings of a symposium presented at the 30th Annual European College of Neuropsychopharmacology Congress, 4 September 2017, Paris, France

Therapeutic Advances in Psychopharmacology ◽

10.1177/2045125318762911 ◽

2018 ◽

Vol 8 (1_suppl) ◽

pp. 1-16 ◽

Cited By ~ 4

Author(s):

Roger S. McIntyre ◽

Allan H. Young ◽

Peter M. Haddad

Keyword(s):

Controlled Trial ◽

Treatment Options ◽

Current Evidence ◽

Simultaneous Occurrence ◽

Affective States ◽

Mixed States ◽

Course Of Illness ◽

Dsm 5 ◽

Opposite Pole ◽

Mixed Features

The simultaneous occurrence of manic and depressive features has been recognized since classical times, but the term ‘mixed state’ was first used by Kraepelin at the end of the 19th century. From the 1980s, until the advent of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), psychiatric disorders were classified using a categorical approach. However, it was recognized that such an approach was too rigid to encompass the range of symptomatology encountered in clinical practice. Therefore, a dimensional approach was adopted in DSM-5, in which affective states are considered to be distributed across a continuum ranging from pure mania to pure depression. In addition, the copresence of symptoms of the opposite pole are captured using a ‘with mixed features’ specifier, applied when three or more nonoverlapping subthreshold symptoms of the opposite pole are present. Mixed features are common in patients with mood episodes, complicating the course of illness, reducing treatment response and worsening outcomes. However, research in this area is scarce and treatment options are limited. Current evidence indicates that antidepressants should be avoided for the treatment of bipolar mixed states. Evidence for bipolar mixed states supports the use of several second-generation antipsychotics, valproate and electroconvulsive therapy. One randomized controlled trial has demonstrated the efficacy of lurasidone, compared with placebo, in patients with major depressive disorder with mixed features, and there is limited evidence supporting the use of ziprasidone in such patients. Further research is required to determine whether other antipsychotic agents, or additional therapeutic approaches, might also be effective in this setting.

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Reassessing Carbamazepine in the Treatment of Bipolar Disorder Clinical Implications of New Data

CNS Spectrums ◽

10.1017/s1092852900023063 ◽

2005 ◽

Vol 10 (6) ◽

pp. 1-2 ◽

Cited By ~ 1

Author(s):

Terence A. Ketter ◽

David L. Ginsberg ◽

Hagop S. Akiskal ◽

Paul E. Keck ◽

Richard H. Weisler ◽

...

Keyword(s):

Bipolar Disorder ◽

Weight Gain ◽

Drug Interactions ◽

Bipolar Depression ◽

Panel Discussion ◽

Current Data ◽

Clinical Implications ◽

Good Tolerability ◽

Long Term Treatment

AbstractThis monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions.Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

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