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Robert J. Haight, PharmD, BCPP
Program Committee Vice Chair

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) introduced “mixed features” as a new specifier for the diagnosis of Major Depressive Episodes (MDE) and Bipolar I and II disorders. Approximately 20 to 40 percent of patients with a major depression diagnosis have experienced subsyndromal symptoms of hypomania but have not been diagnosed with a bipolar disorder. Patients diagnosed with mixed features have increased symptom severity and comorbities. There are no agents approved by the United States, Food and Drug Administraion (FDA) for Major Depressive Episodes with mixed features.

Michael Thase, MD presented on the development of the mixed features specifier and medication treatment options during his presentation, Mixed Opinions? Recognition and Management of Depressions with Mixed Features. Dr. Thase is a Professor of Psychiatry at Perelman School of Medicine of the University of Pennsylvania and also practices at the Philadelphia VA Medical Center.

After he reviewed the differential diagnosis of depressive disorders. Dr. Thase provided additional details on the “with mixed features” specifier. In general, the mixed features specifier applies to any episode in which at least three symptoms are unique to the opposite pole are present. In patients with a major depressive diagnosis, this could include additional symptoms of euphoric or expansive mood, flight of ideas, racing thoughts, grandiosity, and increased energy. These symptoms must be present nearly every day.

He focused on the impact of each patient’s presenting symptoms and “History taking in the age of DSM-5.” Dr. Thase emphasized the importance of assessing for symptoms of depression and hypomania/mania during every patient encounter, especially asking about mood changes immediately prior to and after depressive episodes. He reminded attendees about the importance of obtaining collateral symptom histories from significant others or other family members, specifically regarding fluctuating or episodic changes. When identifying mixed features, certain “clues” in the patient’s history may be relevant, including early age of onset (<30 years), presence of suicidal ideation, history of traumatic brain injury, substance use, multiple prior episodes, and a family history of bipolar disorder.

Patients with MDD with mixed features have additional burdens including higher rates of suicide attempts, greater risk of comorbidities (anxiety, impulse control, and substance abuse disorders), a higher likelihood of coexisting heart disease, and a greater chance of converting to bipolar disorder. Potential consequences of not correctly diagnosing patients with mixed features include:

  • Underestimating the risk of suicide
  • Inappropriate treatment selection
  • Psychosocial burdens
  • Reduced quality of life

Current clinical practice usually includes the initiation of an SSRI or buproprion. If the patient experiences little or no response, switching to a different antidepressant or augmentation with an atypical antipsychotic is recommended. Unfortunately, randomized, placebo-controlled studies of antidepressants for patients with MDD mixed features are lacking. Atypical antipsychotics which have been found to be effective in patients with MDD with mixed features and/or bipolar disorder with mixed features include lurasidone, ziprasidone, and olanzapine.

Take Home Messages:

  • Identification of patients with mixed features may improve outcomes by better informing treatment selection.
  • There are no FDA approved medications for the treatment of major depressive disorder with mixed features.
  • Atypical antipsychotics may be preferred treatment options for patients diagnosed with depressive episodes with mixed features.


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  4. Patkar A, Gilmer W, Pae CU, et al. A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS One. 2012;7(4):e34757 DOI:10.1371/journal.pone.0034757  Epub 2012 Apr 24. PMID: 22545088
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  6. Tohen M, Kanba S, McIntyre RS, et al. Efficacy of olanzapine monotherapy in the treatment of bipolar depression with mixed features. J Affect Disord. 2014 Aug;164:57-62. doi: 10.1016/j.jad.2014.04.003. Epub 2014 Apr 16. PMID: 24856554
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