Exploring the potential of a bridge therapy: Synergistic approach integrating intravenous ketamine and intranasal esketamine for treatment-resistant depression

Depressive disorders represent a significant economic and health burden globally. This is particularly evident in treatment-resistant depression (TRD), commonly defined as the absence of a satisfactory response to at least two different antidepressant trials (as defined by the U.S. Food and Drug Administration/FDA and European Medicine Agencies/EMA). The foregoing TRD cases frequently manifest as complex, difficult-to-treat depression, requiring rapid symptom alleviation and innovative strategies for effective management. Recently, the role of novel glutamatergic agents, including intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS), has been brought into the spotlight for managing TRD. Ketamine, an N-methyl-Daspartate (NMDA) receptor antagonist with effects on multiple cellular and metabolic processes including but not limited to synaptogenesis and brain plasticity, has demonstrated rapid-acting antidepressant effects. Esketamine, the S-enantiomer of racemic ketamine, administered intranasally, has also established efficacy in TRD in replicated several randomized clinical trials (RCTs), being approved by the FDA and the EMA for this indication, and is now considered an evidence-based treatment for TRD. Both treatments have been considered a valuable tool to rapidly alleviate severe depressive symptoms as well as emergency presentations of depression complicated by suicidal ideation or suicide attempts. Recently, KET-IV has been reported to be comparably effective to electroconvulsive therapy (ECT), a treatment traditionally viewed as the most effective approach for treatmentresistant cases. In this perspective article, we propose a “ketamine/ esketamine bridge therapy,” for further empirical testing. The concept of bridge therapy is a well-recognized intervention strategy in internal medicine, particularly applicable to emergent situations associated with coagulation disorders. In these clinical situations, to rapidly achieve anticoagulation, patients are administered intravenous anticoagulants followed by a transition to dose-equivalent oral anticoagulants thereby maintaining tolerability and real-world practice. The notion of considering an approach for further testing like this is provided by recognition of the suboptimal accessibility of intravenous ketamine and the potential for greater scalability of the intranasal formulation. Applying this model to psychiatric clinical practice, we advocate the implementation of “bridge therapy” as a therapeutic strategy for evaluation in TRD subjects and/or in clinical scenarios where on the one hand rapid symptom relief is paramount, yet on the other the need for maintenance of effect with practical approaches persists beyond acute treatment. Conceptually, KET-IV would facilitate rapid antidepressant effects while ESKNS would promote long-term maintenance of effect. The novel therapeutic approach we proposed is suggested by a confluence of study results. Recent findings from real-world studies suggest a latency period to response in persons receiving ESK-NS, with a significant proportion of subjects achieving response even months after the onset of treatment; on the other hand, KET-IV exerts rapid antidepressant effects within the first infusions also in real-world practice. Furthermore, preliminary comparative studies between KET-IV and ESK-NS demonstrate a faster action of the former. As regarding long-term efficacy, there is a substantial research base that confirms the enduring efficacy and acceptability of ESK-NS. On the other hand, the long-term efficacy of KET-IV is not sufficiently studied in TRD. It is empirically established that post-administration bioavailability of KET-IV nearly approximates 100%. In contrast, ESK-NS displays a bioavailability estimated to be around 20%–50%. These pharmacodynamic differences may potentially contribute to variability in the onset of action exhibited by these two formulations. This variation may be especially relevant in clinical practice, notably in patients suffering from more acute presentations, where higher immediate drug bioavailability may be critical for optimal therapeutic effect. In view of these considerations, the “ketamine/ esketamine bridge therapy” is proposed to consist of two distinct phases (Figure 1). The induction phase commences as the patient, within the context of managing a Received: 8 June 2023 Revised: 27 July 2023 Accepted: 7 August 2023