Accurately Diagnosing and Addressing Mixed Episodes in Bipolar Disorder

The process of diagnosing and treating mixed episodes in bipolar disorder (BD) may be complicated by differing presentations of both manic and depressive symptoms. In this video filmed at Psych Congress 2024, faculty member Joseph Goldberg, MD, discusses strategies for effectively identifying and addressing mixed presentations in patients with BD. In addition to highlighting key considerations for making an accurate diagnosis, Dr Goldberg offers practical strategies for managing both depressive and manic symptoms without exacerbating either symptom group. 

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Key Takeaways for Clinical Practice:

• In the DSM-5, mixed features are defined as the presence of opposite-pole symptoms during a manic or depressive episode, requiring clinicians to screen both poles and determine which symptoms predominate.
• Mixed features carry a higher suicide risk than pure depression because increased energy may amplify despair, and antidepressants should generally be avoided as they can worsen agitation or activation.
• FDA-approved treatments for bipolar depression often help mixed features; favor a unified regimen over piecemeal add-ons, note asenapine has data while brexpiprazole lacks it, and correct sleep, substance, stimulant, and adherence issues.

Read the Transcript

Joseph Goldberg, MD: Hi, I'm Dr Joseph Goldberg. I'm a clinical professor of psychiatry at the Icahn School of Medicine in Mount Sinai in New York. I do research in the psychopharmacology of mood disorders and psychotic disorders.

Psych Congress Network: What are the primary challenges in accurately diagnosing mixed episodes in bipolar disorder, given the presence of both manic and depressive symptoms?

Goldberg: Episodes in bipolar disorder often can involve elements of both high and low at the same time. In the DSM-4, we used to conceptualize a mixed state much more narrowly as a full syndrome of mania with a full syndrome of depression. Now in the DSM-5, we only need a few symptoms of the opposite pole along with the syndrome of the other pole to constitute an entity. One of the challenges is knowing to ask systematically the questions about both poles, meaning if someone presents very depressed or very manic, a clinician might be so impressed with what they see in front of them that they may not stop to think, “Wait a minute. I know you're very depressed right now, but at the same time, are you finding your thoughts go really fast through your mind? Do you find that you need less sleep to feel rested the next day? Is your energy up not down?” and vice versa when it comes to someone who's manic who may have depression symptoms. So focus number one is to know, to ask systematically about all the symptoms of both poles. 

A second element is to recognize the predominance of what symptoms that you see. So if someone is profoundly depressed or suicidal, you need to know if mixed features are present because there's something about the energy state of mixed features that could push someone a little more toward impulsively acting on the content of their thoughts. That's one reason why people have said that mixed features are an especially high risk for suicide attempts or completions, even more so than just the pure depressed phase of the illness, because there's this energy that comes with a sense of despair. It’s really important to be mindful about that.

The third piece is the time course, and the trajectory of recovery is different. Mixed features presentations last longer, they're slower to recover. They often also get the wrong treatments. It's been shown antidepressants in general in bipolar disorder tend not to be that helpful, but in mixed features presentations, they can be outright detrimental by driving further some of these agitation features. Those would be some of the things that I'd be thinking about. 

PCN: How can clinicians balance the management of both "highs" and "lows" in a mixed episode without exacerbating either symptom group? 

Goldberg: This really gets to the pathophysiology of a mixed presentation. It is simultaneously the high energy and activation and agitation that comes with the high, paired with the despair and negativism of a low. The way to not go about that is piecemeal. You don't say, “Well, I'll use an antidepressant for the low symptoms and I'll use an anti-manic for the high symptoms.” That's misguided, and one is really aiming for a more consolidated treatment approach that captures the entirety of the presentation. 

The FDA approved treatments for bipolar depression have, for the most part, been shown to have efficacy for mixed features presentations, not just pure depressed phases of illness. There are a handful of additional medicines that also have been shown to have value in mixed features presentations, the totality of both high and low. The drug asenapine has some data in mixed features presentations. 

Some atypical antipsychotics have not been studied for bipolar depression or for mixed features. Brexpiprazole for instance, has no data, so we can't necessarily make a class generalization about atypical antipsychotics. More helpful would be to recognize that these are medications that have been or not been studied in those presentations, and then to really take this comprehensive approach. 

And last but not least, to make sure that you've eliminated any other factors that could be exacerbating the highs or the lows. That can include things like poor sleep, hygiene, alcohol or substance use, misuse or inadvisable use of things like stimulants. If somebody's agitated and activated, they probably don't need to be on amphetamine at the same time. People that are erratic in their medications and are undertreated also put themselves more at risk. So those would be some of the things I would think about.

Joseph F. Goldberg, MD, is Clinical Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai. He attended college at the University of Chicago, graduate school in neuroscience at the University of Illinois, and medical school at Northwestern University. He completed his residency and chief residency in psychiatry, and fellowship in psychopharmacology, at the Payne Whitney Clinic, New York Presbyterian Hospital, where he later served on the faculty and was site Principal Investigator at Weill-Cornell Medical Center for the NIMH STEP-BD program. He has published over 240 peer-reviewed papers on topics related mainly to the treatment and clinical features of bipolar disorder, as well as five books on bipolar disorder and psychopharmacology, most recently, "Clinical Reasoning and Decisio-Making in Psychiatry," with Stephen Stahl, MD,PhD, published in 2024 by Cambridge University Press. He served as President of the American Society of Clinical Psychopharmacology from 2023-2025 and is the Deputy Editor-in-Chief of The Journal of Clinical Psychiatry. His research has been awarded funding from NARSAD, NIMH, the Stanley Foundation, and the American Foundation for Suicide Prevention. Dr. Goldberg is a Distinguished Fellow of the American Psychiatric Association and has been listed for many years in Best Doctors in America and Castle Connolly's "America's Top Doctors."

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