Optimizing Ketamine Infusion Therapy for Treatment‐Resistant Bipolar Depression: Commentary on Zhou et al. (2023)

ABSTRACT

Objectives

To contextualize the real‐world findings of repeated intravenous ketamine infusions for treatment‐resistant bipolar depression (TRBPD) and identify priorities for safer, more durable clinical implementation.

Methods

We provide a focused commentary on Zhou et al. (2023) and integrate selected evidence concerning inflammatory and metabolic correlates, neurocognitive outcomes, and continuation‐phase ketamine treatment.

Results

Repeated subanesthetic ketamine infusions may rapidly improve depressive and anxiety symptoms with an acceptable short‐term safety profile. However, the predictive value of C‐reactive protein and body mass index varies across cohorts; available cognitive findings are reassuring but limited; and relapse after induction highlights the need for individualized maintenance planning.

Conclusions

Ketamine pathways for TRBPD should combine cautious patient stratification, repeatable cognitive monitoring, and explicit continuation or booster strategies. Prospective bipolar‐specific studies are needed to clarify predictors, durability, and stopping rules.

We read with great interest the report by Zhou et al. [1] examining the effectiveness and safety of repeated intravenous ketamine infusions for treatment‐resistant bipolar depression (TRBPD) in real‐world practice. Their findings add clinically relevant evidence supporting ketamine's rapid antidepressant and anxiolytic effects, with generally manageable adverse effects. At the same time, several practical issues warrant further discussion to optimize patient selection, monitoring, and longer term treatment planning.

First, patient stratification remains a priority for translating ketamine protocols into routine practice. Zhou et al. [1] identified younger age, lower baseline C‐reactive protein (CRP), and absence of rapid cycling as favorable predictors, whereas obesity and comorbid anxiety were associated with poorer outcomes. In contrast, Lipsitz et al. [2] did not find pretreatment body mass index (BMI) to predict clinical response among adults receiving repeated intravenous ketamine in a community setting. This divergence illustrates that metabolic and inflammatory correlates may not generalize uniformly across cohorts, diagnostic compositions, or treatment pathways. Pragmatically, these variables may still be useful for shared decision‐making, helping clinicians set realistic expectations and identify subgroups who may benefit from tailored induction and follow‐up intensity.

Second, as ketamine moves further into real‐world use, systematic evaluation of cognition remains essential. Dai et al. [3] reported no evidence of cognitive impairment after repeated ketamine infusions in treatment‐resistant depression, supporting cognitive safety in routine care. However, real‐world samples are heterogeneous with respect to baseline cognitive reserve, concomitant medications, and illness burden. Incorporating brief, repeatable neurocognitive measures (and, where possible, mechanistic studies using functional neuroimaging) could clarify whether specific cognitive domains are affected transiently, improved secondarily to symptom relief, or remain unchanged across repeated infusions.

Third, durability of benefit is a central implementation challenge. Zhou et al. [1] observed substantial relapse within 3 months after induction, emphasizing that acute response does not necessarily translate into sustained remission. Continuation‐phase approaches may be helpful: Vande Voort et al. [4] reported that structured continuation infusions in acute‐phase remitters were associated with extended symptom improvement over subsequent weeks, although careful monitoring is needed in high‐risk patients. Prospective studies are therefore needed to define practical maintenance schedules (e.g., interval length, criteria for booster dosing, and stopping rules) and to determine which patients benefit most from maintenance versus alternative next‐step strategies.

In summary, Zhou et al. [1] provide timely, practice‐oriented data supporting repeated ketamine infusions as an option for TRBPD. Future work should prioritize (i) clinically usable stratification models that incorporate metabolic and inflammatory information, (ii) standardized cognitive monitoring across infusion courses, and (iii) evidence‐based maintenance protocols to improve durability and reduce relapse. These steps will strengthen the clinical applicability of ketamine therapy and support safer, more personalized care for patients with TRBPD.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.