A novel sequential ketamine and D-Cycloserine/lurasidone therapy for bipolar depression with acute suicidal ideation

INTRODUCTION: Bipolar depression with acute suicidal ideation and behavior (ASIB) is a life- threatening manifestation of bipolar disorder (BD), with a suicide risk higher than that in other psychiatric disorders and the general population. Rapid and effective interventions are critical, as traditional therapies are often slow and frequently insufficient. Currently, no drug is approved by the Food and Drug Administration (FDA) to produce rapid anti-suicidal effects in this population. AREAS COVERED: This review examines mechanistic and clinical studies of a two-step therapeutic approach in high-risk bipolar depression. An initial intravenous (IV) ketamine protocol provides rapid symptom relief, followed by a maintenance combination of D- cycloserine (DCS) and lurasidone to maintain therapeutic effects. DCS is a partial N-methyl-D- aspartate (NMDA) receptor agonist, and lurasidone is an FDA-approved treatment for bipolar depression. This strategy represents a mechanistically informed approach to prolong ketamine's therapeutic impact. Relevant trials and mechanistic studies were reviewed to evaluate efficacy, safety, and strategies to extend anti-suicidal benefit. EXPERT OPINION: Despite its mechanistic rationale, uncertainties remain regarding which components drive efficacy, the optimal dosing strategy, and how long benefits last. Further studies are needed to refine maintenance strategies and translate mechanistic insights into effective clinical practice.