Depressive Mixed States: Diagnosis, Treatment, and Strategies

Depressive Mixed States (DMX) is a new specifier listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and describes when patients experience both depressive symptoms and symptoms of mania or hypomania simultaneously. Due to the overlap in symptoms, this condition can be difficult to diagnose. In a Q&A with Psych Congress Network, Mark Zimmerman, MD, previewed his Psych Congress 2023 session "Assessment and Management of Depressive Mixed States," where attendees will learn how to sift out symptoms and better understand the clinical presentation of DMX to get to more accurate diagnoses and successful treatment.

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Evi Arthur, Psych Congress Network: Could you explain the distinguishing features that set Depressive Mixed States (DMX) apart from other psychiatric conditions? What are some atypical symptoms that might be encountered, and how do these contribute to the challenge of accurate diagnosis?

Mark Zimmerman, MD: Mixed features is a new specifier introduced in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) to characterize individuals with mood disorders who have features of the opposite pole from their primary mood episode. That is, in depressed patients the mixed features specifier refers to the presence of manic symptoms that are also present. The mixed features specifier applies to both bipolar depression as well as major depressive disorder. 

The criteria for the DSM-5 mixed features specifier for depressive episodes include 7 manic symptoms, 3 or more of which must be present for the majority of the depressive episode. The 7 symptoms that define the mixed features specifier are: euphoric mood, grandiosity, racing thoughts, hypertalkativeness, increased activity, increased impulsive pleasurable activities, and reduced need for sleep. These symptoms were chosen because they are not also considered symptoms of depression. This has provoked criticism due to the failure to include some symptoms that have classically been considered mixed features—agitation, irritability, and distractibility. 

Another source of disagreement in identifying mixed features is the time frame of their occurrence. DSM-5 requires the presence of the symptoms for the majority of the depressive episode. However, many studies of mixed features require their presence only for the past week. We recently published a study in which we found that reducing the time frame to the past week rather than the majority of the episode resulted in a near-doubling of the prevalence of mixed features.   

Arthur, PCN: What evidence-based treatment approaches have shown effectiveness in managing Depressive Mixed States? How do these approaches differ from treatments for pure depressive episodes or manic episodes, and why is tailoring treatment crucial in DMX?

Dr Zimmerman: There are no FDA-approved medications for the treatment of depressive episodes with mixed features. There are a number of problems with the treatment literature. First, it is limited. There are only 7 placebo-controlled studies of depressed patients with mixed features. Second, most of the studies are post-hoc analyses of studies of bipolar depression. Only 2 studies were prospectively designed to examine the treatment of depression with mixed features and both of these studies lowered to diagnostic threshold to 2 mixed features (rather than 3). Third, the definitions of mixed features varied in the studies and were not consistent with the DSM-5 criteria. 

Keeping these important caveats in mind, the studies have shown that most of the second-generation antipsychotic medications that are FDA approved for the treatment of bipolar depression are also effective in treating depressed patients with mixed features. Moreover, in the post hoc analyses of the studies establishing efficacy for bipolar depression, the efficacy of the medication has been comparable in patients with and without mixed features. 

Two of the 7 studies included patients with major depressive disorder with mixed features. These were the only 2 prospectively designed studies, and 1 study was solely of patients with major depressive disorder (MDD) and the other study included an admixture of patients with MDD and bipolar disorder. Both studies lowered the diagnostic threshold to 2 mixed features, and both excluded patients with more than 3 mixed features. Both studies found a second-generation antipsychotic was effective. 

The other important treatment implication of mixed features is the risk of a manic switch in patients with bipolar depression who are treated with antidepressants. Most official treatment guidelines of bipolar disorder recommend not using antidepressants in patients with bipolar disorder with mixed features. 

Arthur, PCN: Given the complexity of DMX, what strategies do you recommend for clinicians to enhance their assessment skills in recognizing and diagnosing this condition?

Dr Zimmerman: Most important is to recognize bipolar disorder in patients presenting with depression. This requires systematic inquiry of past episodes of mania or hypomania. Just as important, perhaps even more important, is to avoid overdiagnosing bipolar disorder in someone with major depressive disorder. The reason I say perhaps more important is because it is easier to correct a false negative diagnosis than a false positive diagnosis. Some with bipolar disorder who is incorrectly diagnosed with major depressive disorder can have the diagnosis corrected upon emergence of a hypomanic or manic episode. Of course, one should not be cavalier about this and regularly underdiagnose bipolar disorder, but the error can be corrected over time. In contrast, because bipolar disorder is often a historical diagnosis based on past episodes of mania or hypomania, once the diagnosis is made it sticks and is not undone by following the patient over time. In fact, if a mood stabilizer is begun and there is no recurrence of a manic or hypomanic episode one would conclude that the medication prevented future episodes when, in fact, the patient never had an episode in the first place. That is why I say a false negative diagnosis can be corrected whereas a false positive cannot.

Some years ago we modified the self-administered depression questionnaire that we developed to include the features of the DSM-5 mixed features specifier. Thus, one way to improve recognition is to utilize a self-administered questionnaire. More recently, we developed a semi-structured interview for mixed features in depressed patients. The unique features of the DSM-5 Mixed Features Specifier Interview (DMSI) is that it assesses the DSM-5 criteria as well as the features that have classically been considered mixed features but are not included as part of the DSM-5 criteria. Also, symptom severity for the past week can be rated.   

Arthur, PCN: In clinical practice, what challenges do clinicians commonly encounter when treating individuals with Depressive Mixed States? Are there any particular nuances in the therapeutic relationship or treatment planning that need to be considered when addressing this complex condition?

Dr Zimmerman: The biggest challenge for practicing clinicians is having or taking the time to do sufficiently thorough assessments to determine the presence of mixed features. Depressed patients will not typically spontaneously report opposite pole symptoms so direct inquiry needs to be made. It is also important to distinguish mixed features from the mood instability that characterizes borderline personality disorder, but we can reserve an in-depth discussion of that differential for another time. 

Mark Zimmerman, MD, is a professor of psychiatry and human behavior at Brown University and chief of ambulatory psychiatry and behavioral health at South County Psychiatry. Zimmerman received his undergraduate degree from Columbia University, and his medical degree from Chicago Medical School. He completed his postgraduate training at the Medical College of Pennsylvania, and held an academic appointment as assistant professor while he was a resident in psychiatry. Zimmerman is principal investigator of the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project.