Major Depressive Disorder With Mixed Features: Diagnosis and Treatment

Major depressive disorder with mixed features appeared for the first time in the DSM-5. It is defined as meeting criteria for major depressive disorder with 3 or more comorbid manic symptoms (out of 7) on most days of the depressive episode, but the patient does not have a history of mania or hypomania that meets criteria for bipolar disorder.

The final part of this definition is the toughest, because this is a diagnosis that is routinely missed by clinicians, often for many years. I have continued to see this clinically in the US Department of Veterans Affairs when evaluating (by chart review followed by telehealth video interview) over 2000 patients referred for diagnostic consultation over the past 15 years, usually because of the emergence of evidence of possible bipolar disorder. Some of these consultations are also for patients with known bipolar disorder who are not responding to treatment, but it is often evident in their histories that they were treated for many years as if diagnosed with nonbipolar depressions, usually with antidepressants (and they may still be on them). I provided updated suggestions on how to decide whether depressions are bipolar depressions in Psychiatric Times last year.¹ I find that describing mania/hypomania in a 5-to-10-minute narrative that includes real-world examples of the kinds of experiences patients have while covering all of the DSM-5-TR symptoms. The narrative walks through a typical episode from beginning (racing thoughts about new plans and projects) to end (rapid crash into depression). Many patients understand for the first time what mania is and is not, and can easily endorse or reject the description as relevant to their life experience.

Even when, despite your best effort, you cannot find a history of mania or hypomania, the patient might have a “prebipolar depression,” meaning that they are quite likely to eventually have a (hypo)mania at some time in the future, and the diagnosis would then become bipolar disorder. In a review by a consensus panel of experts, several predictors of eventual conversion to bipolar disorder were identified, any of which might suggest that the current depression should be treated with bipolar depression treatments. These included a family history of bipolar disorder, a younger age of onset, anxiety that reaches panic levels, a family history of completed suicide, a history of treatment-emergent irritability, agitation or suicidality after previous antidepressant treatments, depression that also has psychotic features, and postpartum psychosis.² In addition, depression with atypical features (hypersomnia, hyperphagia with weight gain, leaden paralysis, and rejection sensitivity) is also very common in bipolar depressions.³ Those with a seasonal pattern of depressions can also be at risk for bipolar disorder.⁴ Also, for reasons not well understood, many patients with bipolar disorder have a history of migraine headaches, so seeing migraines in the medical problem list might immediately raise suspicion that the patient has a bipolar depression.⁵

However, if none of these reasons are present that might encourage use of bipolar medications to treat major depression with mixed features, there seems to be an emerging consensus that you should treat with bipolar depression medications anyway. Two FDA-approved treatments for bipolar depression have placebo-controlled positive trials in major depressive disorder with mixed features: lurasidone and lumateperone.^6,7 Note that in the lurasidone study, the criteria for depression with mixed features required only 2 (or more) manic symptoms, rather than the DSM-5-TR criteria requirement of 3. In the lumateperone study, the number needed to treat was 4, which is quite impressive. A 2025 systematic review considered all the available evidence and found, in addition to these 2 medications, support for olanzapine, cariprazine, quetiapine, and ziprasidone, but only from post hoc data.⁸ Lithium and valproate monotherapy had not been adequately studied, but these agents do not appear to be effective as monotherapy for bipolar depression,¹ so it does not seem likely that they would be effective for depression with mixed features. Antidepressant monotherapy (with standard antidepressants) has essentially not been studied.

Based on the limited evidence available, psychopharmacological treatment for depression with mixed features should perhaps consist of the same medications used for bipolar depression, while avoiding antidepressants. The recommended initial treatments for bipolar depression are the same in both the latest VA/DoD bipolar disorder practice guideline and in the Harvard South Shore Psychopharmacology Algorithm Project bipolar depression algorithm: quetiapine, lurasidone, cariprazine, lumateperone, and the combination of lithium and lamotrigine.^1,9 One should choose the treatment that seems to fit best with the patient’s medical condition, considering predicted vulnerability to adverse effects, patient preference, and local availability. Cariprazine and lumateperone are still very expensive and may be restricted. In the event of poor response or intolerance, try others from among these 5 options until all that are suitable have been tried. If there is still unsatisfactory response, one could then try a standard antidepressant (such as bupropion or a selective serotonin reuptake inhibitor), but one would still avoid an antidepressant if there is rapid cycling in and out of these depressive mixed states, or a history of worsening of the condition with previous antidepressants that may have been tried. In that case, one would instead try various combinations of the 5 initially recommended medication regimens, and then consider a variety of options for treatment-resistant bipolar depression that have limited evidence.

There is a pressing need for further research on the treatment of major depressive disorder with mixed features.

Dr Osser is associate professor of psychiatry at Harvard Medical School, VA Boston Healthcare System, Brockton Division, and lead psychiatrist in the VA National Bipolar Disorders Telehealth Program.

References

1. Osser DN. How to decide whether depressions are bipolar depressions. Psychiatric Times. 2025;42(3).

2. Faedda GL, Baldessarini RJ, Marangoni C, et al. An International Society of Bipolar Disorders task force report: precursors and prodromes of bipolar disorder. Bipolar Disord. 2019;21(8):720-740.

3. Bowden CL. Strategies to reduce misdiagnosis of bipolar depression. Psychiatr Serv. 2001;52(1):51-55.

4. Byrne EM; Psychiatric Genetics Consortium Major Depressive Disorder Working Group; Raheja UK, Stephens SH, et al. Seasonality shows evidence for polygenic architecture and genetic correlation with schizophrenia and bipolar disorder. J Clin Psychiatry. 2015;76(2):128-134.

5. Sekula NM, Yocum AK, Anderau S, McInnis MG, Marshall DF. Lithium use associated with symptom severity in comorbid bipolar I and migraine. Brain Behav. 2022;12(6):e32585.

6. Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind placebo-controlled study. Am J Psychiatry. 2016;173(4):400-407.

7. Durgam S, Kozauer SG, Earley WR, et al. Lumateperone for the treatment of major depressive disorder with mixed features or bipolar depression with mixed features: a randomized placebo-controlled trial. J Clin Psychopharmacol. 2025;45(2):67-75.

8. Xiao N, Yin L, Lee S, et al. The efficacy of pharmacological interventions in the treatment of major depressive disorder and bipolar depression with mixed features: a systematic review. Bipolar Disord. 2025;27(5):347-357.

9. Osser DN. Chapter 2: The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression. In: Psychopharmacology Algorithms. 2nd Ed. Wolters Kluwer; 2026:7-46. Updated from Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression. Bipolar Disord. 2020;22(5):472-489.