01. Lumateperone for Depression with Mixed Features: Is It Effective?

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Lumateperone for Major Depression with Mixed Features

Today, we’re exploring the treatment of major depressive episodes with mixed features.

This subset of patients experiences symptoms typically seen in mania or hypomania while depressed, such as racing thoughts, feeling keyed up, or restless energy. The DSM-5 defines this as a major depressive episode with mixed features, applicable to both major depression and bipolar disorder diagnoses.

Identifying mixed features is crucial clinically. These patients often face:

• A tougher course
• More severe illness
• Higher likelihood of comorbid conditions
• Greater suicide risk

And let’s be honest, treating them can feel like walking a tightrope, because you’re always thinking about whether a treatment might accidentally tip them into a full manic or hypomanic episode.

That brings us to a recent study.

Lumateperone Study Design Overview

A randomized, double-blind, placebo-controlled trial published in the Journal of Clinical Psychopharmacology in April 2025 examined Lumateperone 42 mg for treating major depressive episodes with mixed features in patients with major depression or bipolar depression. I just love this because not enough studies look at mixed features, and this patient population really deserves more attention.

The study enrolled adults aged 18 to 75 experiencing a major depressive episode, with at least three manic or hypomanic symptoms during most days of their depressive episode. Importantly, these symptoms were not enough to meet full criteria for mania or hypomania. Patients also needed to be at least moderately depressed at the start.

They were split into two groups: one got lumateperone 42 mg daily, and the other got placebo for six weeks. The trial lasted six weeks, using the MADRS (Montgomery-Asberg Depression Rating Scale) and CGI-S (Clinical Global Impressions Scale-Severity) to measure outcomes.

Primary Efficacy Results: Significant Improvement in Depression

The study revealed that lumateperone 42 mg significantly improved depression symptoms based on MADRS scores by the end of six weeks compared to placebo. This benefit was observed in both MDD and bipolar depression patients with mixed features.

Patients on lumateperone were more likely to have a MADRS response (at least a 50% drop in depression scores):

• 60% of lumateperone group
• 40% of placebo group

Remission rates were also higher with lumateperone:

• 40% of lumateperone group
• 20% of placebo group

Also, I found it interesting that improvements in depression compared to placebo became significant at day 15. These improvements continued over the rest of the six weeks.

Study Funding Considerations

Now, it’s worth noting that the study was funded by the pharmaceutical company that makes lumateperone, with multiple authors being full-time employees of the company. That doesn’t invalidate the findings.

Industry-funded research is often really necessary to get trials off the ground, but it does mean we should pay close attention to how the study was designed, what outcomes were chosen, and how the results were interpreted.

To their credit, the authors used randomized design. Study participants came from 49 global sites, and the study team remained blinded throughout the study. As clinicians, it’s our job to weigh the evidence on its merits while staying mindful of who stands to benefit. That includes considering what wasn’t studied or how findings might have looked in a different population or comparator.

So let’s dig into one of the potential issues that came up for me, and I’ll give you some of my non-pharma thoughts from the study.

Timeline of Improvement

Now, it’s not totally clear from the study about the degree to which side effects, partially unblinding the drug versus placebo, played a role in the relatively early effects.

The authors note that when they basically excluded the patients who experienced the greatest side effects, there was still significant improvement of lumateperone over placebo at day 43. However, it was not so clear about the relative impact of functional unblinding specifically on the day 15 data.

So to me, with one of my patients in front of me and based on the study graphs, I would likely tell my patient that a good number of people will start to notice improvements and have some significant benefit after just a couple of weeks of lumateperone. They should expect further improvements for several weeks after. The difference in MADRS scores of the placebo group versus lumateperone group at day 15 wasn’t clinically large enough though to be able to confidently recommend to a patient to switch off lumateperone just yet if they weren’t noticing major changes at the two-week mark. I’d hold out for at least a month to see if the medication is having good effect or not.

Mixed Features Response

Now, let’s talk about those tricky mixed features themselves. They used the YMRS (Young Mania Rating Scale) to track those hypomanic symptoms.

Lumateperone significantly reduced YMRS scores compared to placebo. This reduction in mixed symptoms also showed up pretty early—by day 8 or 15 depending on the group—and lasted through the study.

Here’s a major clinical pearl for this population: the study authors explicitly stated that there were no treatment-emergent adverse effects of mania or hypomania reported with lumateperone. That’s huge when you’re concerned about triggering mood switches when trying to get a patient out of depression.

Lumateperone Safety Profile

Lumateperone was generally well tolerated. The most common side effects that were more frequent with lumateperone than placebo were:

• Drowsiness
• Dizziness
• Nausea

Most of these side effects were mild or moderate. Most people recommend first trying lumateperone at night, given the potential for sedation and dizziness.

Another really important clinical pearl, especially when you’re thinking about using an antipsychotic: the study reported minimal EPS. Measures for akathisia and parkinsonism were low and similar to placebo rates.

Regarding metabolic side effects, they found no meaningful changes in weight, body shape, or key metabolic markers like cholesterol, glucose, insulin, or prolactin. This is a significant advantage, especially since patients with mixed features may already have higher rates of other health problems, including obesity.

However, I’m going to look at much longer-term data to get a full picture of long-term side effects. But overall, from other studies, lumateperone does better in these categories than its antipsychotic predecessors.

Suicidal thinking didn’t occur more often with lumateperone, and no one in either group had suicidal behavior during the study.

Clinical Implications

So to wrap it up, for those patients you see with a major depressive episode who also have at least three subsyndromal manic or hypomanic symptoms, whether they have MDD or bipolar disorder, this study suggests lumateperone at 42 mg is effective. It helped significantly improve their depression symptoms and those subsyndromal manic symptoms without pushing them into a full manic episode, which is a major clinical worry in this group.

Plus, it showed a good safety profile, particularly regarding EPS and metabolic side effects when measured at six weeks. The study authors feel these findings make lumateperone 42 mg a promising treatment option for this challenging patient population. Of course, keep in mind it was a six-week study, and it didn’t include patients with really severe suicidal risk or treatment-resistant illness. Always consider those factors in your own practice.

Lumateperone is unique as it is typically dosed just at the 42 mg dose, which can be the starting dose for a patient as well, so no need for titration. For those with major liver issues or significant issues with tolerability, there’s also a 21 mg dose that you can prescribe.

While it’s a newer medication, which means that insurance coverage can be variable, I’ve had really good success seeing insurance cover this drug when patients have first trialed other FDA-approved medications for their depressive episodes.

Thank you for joining me in this Quick Take. I’ll catch you next time with more updates on bipolar research that can make a difference in how we care for our patients.

Abstract

Lumateperone for the Treatment of Major Depressive Disorder With Mixed Features or Bipolar Depression With Mixed Features: A Randomized Placebo-Controlled Trial

Durgam, Suresh M.D.; Kozauer, Susan G. M.D.; Earley, Willie R. M.D.; Chen, Changzheng Ph.D.; Huo, Jason Ph.D.; Lakkis, Hassan Ph.D.; Stahl, Stephen M.D., Ph.D.; McIntyre, Roger S. M.D.

Background 

This randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifer NCT04285515) evaluated efficacy and safety of lumateperone to treat major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features.

Procedures 

Patients (18–75 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)–defined MDD with mixed features (n = 185) or bipolar disorder with mixed features (n = 200) and experiencing an MDE were randomized 1:1 to 6-week placebo (n = 195) or lumateperone 42 mg (n = 193). Primary and key secondary endpoints were change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale Total and Clinical Global Impression Scale-Severity (CGI-S) scores in 3 populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression. Safety included adverse events (AEs), extrapyramidal symptoms, and laboratory parameters.

Results 

Lumateperone met the primary endpoint, significantly improving Montgomery-Åsberg Depression Rating Scale total score at day 43 in populations with combined MDD/bipolar depression (least squares mean difference vs placebo [LSMD], −5.7; 95% confidence interval [CI], −7.60,−3.84; effect size [ES], −0.64; P < 0.0001), MDD (LSMD, −5.9; 95% CI, −8.61,−3.29; ES, −0.67; P < 0.0001), and bipolar depression (LSMD, −5.7; 95% CI, −8.29,−3.05; ES, −0.64; P < 0.0001). Lumateperone significantly improved CGI-S and Young Mania Rating Scale total scores at day 43 in these populations. Lumateperone was well-tolerated. Treatment-emergent AEs (≥5%, twice placebo) in the combined population were somnolence (placebo, 1.6%; lumateperone, 12.5%), dizziness (placebo, 2.1%; lumateperone, 12.0%), and nausea (placebo, 1.6%; lumateperone, 9.9%). There were no mania/hypomania treatment-emergent AEs with lumateperone and minimal extrapyramidal symptoms or metabolic risk.

Conclusions 

Lumateperone 42 mg significantly improved depression symptoms and disease severity and was generally safe and well-tolerated in patients with MDD or bipolar depression with mixed features.

Reference

Suresh, D. M.D.; Susan, K. M.D.; Willie, E. M.D.; Changzheng, C. Ph.D.; Jason, H. Ph.D.; Hassan, L. Ph.D.; Stahl, S. M.D., Ph.D.; McIntyre, R. M.D. (2025).

Lumateperone for the Treatment of Major Depressive Disorder With Mixed Features or Bipolar Depression With Mixed Features: A Randomized Placebo-Controlled Trial

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Journal of Clinical Psychopharmacology

45(2):p 67-75, 3/4 2025.