Bipolar Disorder With Mixed Features: Recognition and Treatment, With Roger McIntyre, MD, at APA

CONFERENCE REPORTER

At the annual meeting of the American Psychiatric Association, held May 16–20 in San Francisco, California, Roger McIntyre, MD, presented a clinically focused review of mixed features in bipolar disorder.¹ His core advice for clinicians was to practice personalized medicine through deep in vivo characterization of every patient, assessing phenomenology, illness course, trauma history, comorbidities, treatment response, and socioeconomic context. Until validated biomarkers are available to guide clinical decision-making, this kind of rigorous, individualized characterization is the most powerful diagnostic tool available.

Prevalence and the Clinical Reality of Mixed Features

Mixed features (defined by DSM-5 as the presence of 3 or more opposite-polarity symptoms concurrent with a full mood episode) apply across mania, hypomania, and depression, and across both bipolar disorder and major depressive disorder (MDD).² Based on data from McIntyre’s ongoing collaborative research, mixed features meeting DSM-5 criteria are present in approximately 25% to 35% of depressive episodes, he said. Some data showed approximately 70% of patients with bipolar depression had at least some hypomanic symptoms, leading McIntyre to emphasize that “pure” bipolar depression without concomitant subthreshold mania is rare.³ Mixed features are more common in women than men, more prevalent in bipolar II than bipolar I disorder, and occur at higher rates in rapid cycling and ultra-rapid cycling states.⁴ Earlier age at onset is associated with greater likelihood of mixed presentation, as is a history of childhood trauma.⁵

Ecological Validity

McIntyre challenged the ecological validity of the prior DSM-IV mixed episode construct, which required simultaneous full mania and full depression, noting that clinicians widely reported not encountering this presentation in practice. The DSM-5 mixed features specifier addressed this by lowering the threshold to 3 or more opposite-polarity symptoms, and by extending applicability to depression, hypomania, and MDD.

The 4 A’s Alerting Mixed Features

To bridge this gap between DSM criteria and clinical reality, McIntyre shared what he calls the “4 A’s” as a practical framework of indications for mixed features: anxiety, agitation, anger or irritability, and attentional disturbance. McIntyre also proposed anhedonia as a potential 5th “A,” noting emerging evidence of its relevance in this population and data suggesting that certain pharmacological agents may specifically target anhedonia in the context of mixed features.

He noted that patients may present having self-diagnosed attention-deficit/hyperactivity disorder (ADHD) and that prescribing psychostimulants to these patients carries real risk. While stimulants do not uniformly destabilize all patients with bipolar disorder, they are destabilizing specifically in those with rapid cycling or mixed features.⁶

Need for a Timely Differential Diagnosis

Clinicians must take care not to confuse bipolar disorder with mixed features for: the anxious distress course specifier, comorbid anxiety or substance use disorders (the most common psychiatric comorbidities in bipolar disorder), autonomic hyperarousal from posttraumatic stress disorder (PTSD), akathisia, or mood instability attributable to comorbid personality disorders, particularly borderline personality disorder. McIntyre identified dysregulated arousal following trauma as among the most diagnostically challenging similar presentations that can be difficult to separate from mixed features without careful history-taking.

McIntyre summarized the clinical burden that patients with mixed features have greater illness severity, longer duration of episodes, lower rates of remission, higher chronicity, higher recurrence, greater comorbidity, and markedly elevated suicidality.⁷ From a biological standpoint, patients with mixed features show greater dysregulation of the hypothalamic-pituitary-adrenal axis, greater autonomic dysregulation, and greater activation of the innate and adaptive immune-inflammatory system compared with nonmixed bipolar presentations.

Assessment Tools for Mixed Features

McIntyre recommended several validated instruments for clinical assessment of mixed features and bipolar disorder. For screening, the online Rapid Mood Screener (RMS) has been validated for bipolar 1 and bipolar 2 disorder and can serve as an efficient triage tool; a positive screen should prompt deeper clinical evaluation rather than serve as a standalone diagnostic conclusion. Additional tools McIntyre highlighted include the Bipolar Depression Rating Scale (BDRS), the Mini International Neuropsychiatric Interview (MINI), the Clinically Useful Depression Outcome Scale with DSM-5 Mixed Features (CUDOS-M), and the Hypomania Checklist (HCL).^8,9 Across all tools, McIntyre emphasized that a positive result should prompt deeper clinical inquiry into age at onset, family history, phenomenology, comorbidities, and treatment response history.

Treatments Options To Use and To Avoid

McIntyre emphasized that data show antidepressants are the most frequently prescribed drug class in bipolar disorder, but patients with mixed features often experience inefficacy or destabilization, as those with low-grade subthreshold mania are particularly vulnerable to destabilization on antidepressants.¹⁰ McIntyre pointed out that most of these patients receive antidepressants as monotherapy, characterizing this as a significant quality gap. Similarly, valproate lacks evidence of efficacy in bipolar depression or long-term maintenance, and carries substantially higher risks of teratogenicity.¹¹

The FDA has approved 5 second generation antipsychotics for bipolar depression.¹² McIntyre reviewed the evidence base for agents specifically studied in mixed presentations, noting that most data derive from post-hoc analyses rather than a priori mixed-features trial designs, which is a methodological limitation to keep in mind.

Medications reviewed included:

• Cariprazine: studied across both poles and has shown efficacy in mania with mixed features, mania without mixed features, bipolar depression with mixed features, and bipolar depression without mixed features.
• Lumateperone, lurasidone: studied in bipolar depression with mixed features.
• Aripiprazole, brexpiprazole, iloperidone: studied in mania with mixed features.
• Olanzapine: studied across both poles.
• Olanzapine-samidorphan: demonstrated efficacy in mania with mixed features, offers reduced weight and cardiometabolic liability relative to olanzapine alone.
• Quetiapine: some data for mixed presentations.

McIntyre highlighted that these agents differ meaningfully in tolerability, potential weight gain, and metabolic effects, and that these differences should inform individualized treatment selection.

McIntyre identified lumateperone as the subject of the only randomized, double-blind, placebo-controlled trial designed a priori to enroll exclusively patients with mixed features—including both unipolar and bipolar 1 and 2 patients—demonstrating statistically significant improvement over placebo at 6 weeks.¹³ He also discussed xanomeline-trospium (Cobenfy) as an agent under investigation for bipolar mania and mixed features.¹⁴

Concluding Thoughts

McIntyre closed by reiterating a practical treatment sequencing framework: for patients with depression in whom he suspects mixed features, he avoids or deprioritizes antidepressants and considers second generation antipsychotics or lithium; for patients with MDD who fail to respond to an adequate antidepressant trial, the presence of mixed features should prompt reconsideration of diagnosis and pivot toward a second generation antipsychotic.

McIntyre highlighted the continuing work needed in personalized medicine and biomarker testing for bipolar disorder with mixed features, and noted ongoing investigation of glucagon-like peptide-1 (GLP-1) receptor agonists as potential mood-stabilizing agents. Until biomarkers are available for clinical use, he argued, the most powerful tool available to clinicians is a thorough, individualized assessment of every patient.

References

1. McIntyre R. Mixed Features in Persons with Depressive and Bipolar Disorder: Historical Conceptual Nosological and Clinical Implications. Conference Proceedings of the American Psychiatric Association. May 2026;16-20. San Francisco, CA.

2. Mixed features specifier. American Psychiatric Association. 2013. Accessed May 20, 2026. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/DSM/APA_DSM-5-Mixed-Features-Specifier.pdf

3. Goldberg JF, Perlis RH, Bowden CL, et al. Manic symptoms during depressive episodes in 1380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166(2):173-81.

4. Lam A. Bipolar disorder in men and women: what’s the difference? International Bipolar Foundation. Accessed May 20, 2026. https://ibpf.org/articles/bipolar-disorder-in-men-and-women-whats-the-difference/

5. Quidé Y, Tozzi L, Corcoran M, et al. The impact of childhood trauma on developing bipolar disorder: current understanding and ensuring continued progress. Neuropsychiatr Dis Treat. 2020;16:3095-3115.

6. Muneer A. Mixed states in bipolar disorder: etiology, pathogenesis and treatment. Chonnam Med J. 2017;53(1):1-13.

7. Solé E, Garriga M, Valentí M, Vieta E. Mixed features in bipolar disorder. CNS Spectr. 2017;22(2):134-140.

8. Li X, Fei Y, Yang H, et al. Reliability and validity of clinically useful depression outcome scale identifying mixed features in patients with manic episode. Brain Behav. 2021;11(8):e2313.

9. Rapid Mood Screener. Accessed May 20, 2026. https://www.rapidmoodscreener.com/

10. Pardossi S, Fagiolini A, Cuomo A. Antidepressants in bipolar depression: from neurotransmitter mechanisms to clinical challenges. Actas Esp Psiquiatr. 2025;53(3):621-631.

11. Mulryan D, McIntyre A, McDonald C, et al. Awareness and documentation of the teratogenic effects of valproate among women of child-bearing potential. BJPsych Bull. 2018;42(6):233-237.

12. Christian R, Saavedra L, Gaynes BN, et al. Tables of FDA-approved indications for first- and second-generation antipsychotics. Future Research Needs for First- and Second-Generation Antipsychotics for Children and Young Adults. 2012.

13. 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.

14. McIntyre RS. Acetylcholine and muscarinic receptor targeting in bipolar disorder: does xanomeline-trospium chloride and other investigational muscarinic agonists hold promise as mechanistically informed treatments for manic episodes, mixed features and cognitive deficits in bipolar disorder? Expert Opin Investig Drugs. 2025;34(6):519-526.