Newer Agents, New Advantages: Brexpiprazole, Cariprazine, and Lumateperone in MDD

In "Newer Agents, New Advantages: Brexpiprazole, Cariprazine, and Lumateperone in MDD," the mental health experts examined the following critical questions:

Brexpiprazole was approved in 2015 and has a relatively favorable tolerability profile compared to aripiprazole, particularly lower akathisia rates. Walk us through the pivotal trial data and how brexpiprazole has been positioned clinically.

Cariprazine received FDA approval for adjunctive major depressive disorder (MDD) treatment in December 2022 and brought a unique D3-preferring partial agonist mechanism to the class. What does the Phase 3 evidence show for cariprazine's efficacy and safety profile?

Lumateperone received FDA approval for adjunctive MDD in November 2025, making it the newest agent in the class. What did the clinical trial establish about its safety and efficacy, and what is its distinguishing pharmacologic profile?

Led by the moderator, the panelists discussed brexpiprazole's pivotal two-phase trial design and how its reduced intrinsic dopamine partial agonism and lower starting doses contributed to fewer akathisia events than aripiprazole, followed by cariprazine's D3-preferring mechanism and more favorable metabolic and sedation profile. They closed by reviewing lumateperone's Phase 3 data, which showed an essentially placebo-level weight gain signal alongside a robust efficacy improvement over placebo, positioning it as a notable addition to the adjunctive treatment armamentarium.

Throughout the conversation, the experts provided a comprehensive reflection on the field and the factors that may shape how clinicians approach care moving forward.

Our next episode, "Comparing Safety Across the Class: Tolerability Trade-offs and Durability of Response," further explores major depressive disorder, highlighting network meta-analysis data comparing weight gain and akathisia risk across the five adjunctive agents, payer perspectives on step therapy policy, and the long-term evidence gaps shaping decisions around relapse prevention and treatment discontinuation.