Prevalence and Illness Characteristics of the “Mixed Features Specifier” in Adults With Major Depressive Disorder & Bipolar Disorder: Results From the International Mood Disorders Collaborative Project

Many patients with mood disorders present with subsyndromal features of mixed states that may differ from their primary diagnoses. This study aimed to assess the prevalence and characteristics of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)-defined mixed features specifier (MFS) in adults with major depressive disorder (MDD) and bipolar disorder (BP).

Why was the research needed?

The DSM-5 introduced the MFS to refine the diagnostic criteria of patients with MDD and BP that are exhibiting subsyndromal features of mixed states. These patients may experience manic or hypomanic symptoms during a major depressive episode (MDE). Alternatively, it can present as depressive symptoms occurring during a manic or hypomanic episode.⁴ Previous studies have indicated that mixed features are associated with a more severe clinical presentation and negative health outcomes.⁵ Research on the prevalence and associated characteristics of DSM-5-defined mixed features in a ‘real-world’ clinical setting may help healthcare providers to identify patients with mood disorders with mixed features and provide appropriate management.

What did the researchers do?

The International Mood Disorders Collaborative Project (IMDCP), a multi-site, naturalistic, cross-sectional study, was conducted at specialized tertiary care centers at the University of Toronto’s Mood Disorders Psychopharmacology Unit and the Cleveland Clinic Center in Cleveland, Ohio.⁶

The analysis included a total of 982 adult patients who met the following inclusion criteria⁶:

• A DSM-4 diagnosis of MDD (n = 573), bipolar I disorder (BP-1; n = 255), or bipolar II disorder (BP-2; n = 154)
• A current MDE or manic/hypomanic episode as per the Mini-International Neuropsychiatric Interview for DSM-4-TR (MINI Plus 5.0)
• A completed Young Mania Rating Scale (YMRS) if the patient was experiencing a current MDE and/or
• A completed Montgomery-Åsberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAMD-17) if the patient was experiencing a manic/hypomanic episode.

The diagnosis of MFS according to the DSM-5 criteria was based on a score of ≥ 1 on 3 or more select items from the YMRS or select depression items from the MADRS or the HAMD-17 during a current MDE or manic or hypomanic episode, respectively.

The severity of MFS was determined as mild, moderate, or severe when a participant scored ≥ 1, ≥ 2, or ≥ 3 on 3 or more items on the YMRS or MADRS/HAMD-17 during an MDE or manic/hypomanic episode, respectively.⁶

The researchers performed post-hoc analyses of the MFS prevalence rate, demographics, illness characteristics, and comorbidity in individuals with MDD, BP-1, and BP-2.⁶

What were the key results of the study?

In terms of the study demographics, participants were 87.70% Caucasian, 6.38% Black/African American, 2.97% Asian, and 2.97% other races. The percentages of female participants were 65.1% for MDD patients, 62.8% for BP-MDE patients, and 58.9% for BP-mania or hypomania patients.⁶ No differences in sex, education, race, or marital status were found between the comparison groups. However, the mean age of patients with mixed features was higher in the MDD group than in the BP group, with 46 years being the mean age of MDD-MFS patients versus 37.9 years for BP-MDE-MFS patients and 38.6 years for BP-mania/hypomania-MFS patients. In addition, a higher rate of unemployment or disability was reported in patients with mixed features.⁶

A significant proportion of both MDD and BP participants met the criteria for MFS. The results showed that 26.0%, 34.0%, and 33.8% of patients diagnosed with MDD, BP-1, and BP-2, respectively, met the criteria for MFS during an MDE, with mixed features being more prevalent in BP patients than in MDD patients. During a manic or hypomanic episode, 20.4% and 5.1% of patients with BP-1 and BP-2, respectively, met the criteria for MFS (Table 1).⁶

Researchers found that the presence of mixed features was associated with more severe depression. In MDD patients, the mean HAMD-17 and MADRS scores were 24.9 and 35.7 for patients with mixed features versus 21.2 and 31.5 for patients without mixed features, respectively. In BP patients with MDE, the mean HAMD-17 and MADRS scores were 23.1 and 31.1 for patients with mixed features versus 21.2 and 30.9 for patients without mixed features, respectively.⁶ The severity of depression in MDD patients exhibiting mixed features was greater than that in BP patients experiencing MDEs regardless of whether they had mixed features or not. There was no difference in YMRS severity in patients with or without mixed features as part of a manic or hypomanic episode.⁶

Table 1. Prevalence of DSM-5 mixed features specifier by severity in MDD, BP-1, and BP-2.⁶ 

When illness characteristics were compared between groups, a diagnosis of MDD with mixed features was shown to be associated with a higher prevalence of psychotic features, poorer workplace productivity, a higher number of lifetime depressive episodes, and a longer time to treatment than MDD without mixed features. However, the differences did not persist when adjusted for multiple comparisons.⁶

There were significant differences in age at illness onset, number of depressive episodes, and duration of illness. However, they were shown to be mainly due to the differences between the MDD and BP disease states. The number of lifetime manic or hypomanic episodes, hospitalizations, suicide attempts, or pharmacologic interventions were not significantly different between comparison groups.⁶

In terms of comorbidities, BP patients with mixed features, but not MDD patients, reported higher rates of alcohol/substance use disorder than participants without mixed features.⁶ All participants with mixed features were more likely to have coexisting heart disease, which suggests a possible pattern of comorbidity and neurobiology. No differences in body mass index, prevalence of diabetes mellitus type 2, autoimmune disease, or total number of concurrent chronic medical conditions were found between the comparison groups.⁶

The numbers of both current and lifetime (experienced at any point in life) psychiatric comorbidities were higher in all BP patients compared with MDD patients without mixed features.⁶ Of the BP patients, those with mixed features as part of an MDE had significantly more lifetime psychiatric comorbidities than MDD patients with mixed features. The numbers of current and lifetime psychiatric comorbidities were also higher in BP patients in a manic or hypomanic episode with mixed features than in all MDD patients. However, they were not higher than the numbers in BP-MDE patients with mixed features or BP patients without mixed features.⁶

Limitations

Limitations of the study were⁶:

• All participants received a post-hoc diagnosis of MFS, rather than a diagnosis initially based on DSM-5 criteria.
• The participants’ data on demographics, illness severity, clinical characteristics, comorbidities, and treatment regimens were heterogenous (but the authors also construed this to be a strength, as it reflects the heterogeneity of disease).
• The study did not have an adequate sample size to analyze the differences between BP-1 and BP-2 patients.
• The researchers did not examine the presence of irritability and agitation, which are common symptoms in BP patients but not listed as criteria for MFS in the DSM-5.

Why are these results important?

The results of this study suggest distinct clinical characteristics and comorbidity patterns in individuals with mood disorders and mixed features. A significant proportion of MDD and BP patients (approximately 25% to 35% of the study participants) exhibited mixed features during an MDE.⁶ It was also shown that patients with mixed features demonstrated more severe depression, higher rates of alcohol/substance use disorder if they had BP, and a higher likelihood of co-existing cardiovascular disease. Health behaviors such as poor diet, limited exercise, and use of cigarettes and/or alcohol may contribute to the higher rate of coexisting cardiovascular disease observed in patients with BP.⁷ These findings are in line with previous studies that have found that BP patients with mixed features are associated with poorer patient outcomes.^8-10 The results of this study highlight the need to carefully evaluate patients for mixed presentations to enable a timely diagnosis and appropriate management of their symptoms, which may help improve outcomes.

What’s next?

Additional randomized, well-controlled trials in adults with mixed features as part of MDD and BP are needed. Interventional studies with treatment and prevention strategies may be beneficial in patients who experience mixed features as part of their MDD or BP.⁶

This resource is intended for educational purposes only and is intended for US healthcare professionals. Healthcare professionals should use independent medical judgment. All decisions regarding patient care must be handled by a healthcare professional and be made based on the unique needs of each patient.   

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