Ketamine and Esketamine in Psychiatry: A Comparative Review Emphasizing Neuroplasticity and Clinical Applications

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled "Ketamine and Esketamine in Psychiatry: A Comparative Re-2 view Emphasizing Neuroplasticity and Clinical Applications" is generally well written and organized.

However, some concerns should be addressed before publication:

- From point n 8-9-10 it seems a new manuscript (or copy-and-paste from other source), having repetitions or acronym explanation previouly done (es lines 293-295)

- Similarly the n10 "conclusions" sounds a novel, repeating, abstract, and it should be reduced as intended, to conclude.

- The title mentions "Neuroplasticity and Clinical Applications". However, the neuroplasticity is merely mentioned (while Clinical Applications  are well described). I suggest to expand the "neuroplasticity part" or, alternatively, to tone down the title.

- Check for some mistypes in figure 1.

 

 

 

 

Author Response

Thank you for your constructive feedback on the manuscript entitled "Ketamine and Esketamine in Psychiatry: A Comparative Review Emphasizing Neuroplasticity and Clinical Applications." We appreciate your time and valuable suggestions, which have helped us improve the quality and clarity of the manuscript.

1. Repetitions and Acronym Reintroduction (Points 8–10):
We have carefully revised Sections 8 and 9, to eliminate redundancy and repetition. Repeated definitions and explanations (e.g., enantiomeric composition and bioavailability) have been removed, and the flow has been streamlined for coherence.

2. Conclusion Section:
The Conclusion has been significantly condensed and restructured to avoid overlap with previous content. It now serves as a concise synthesis of the main findings and implications, consistent with its intended purpose.

3. Title Adjustment and Neuroplasticity Expansion:
In response to your observation about the limited coverage of neuroplasticity, we have expanded Section 3 to include additional detail regarding imaging studies and neuroplastic mechanisms. Alternatively, we have revised the manuscript title to reflect the balanced focus more accurately:
New Title: "Ketamine and Esketamine in Psychiatry: A Comparative Review of Mechanisms, Clinical Applications, and Emerging Therapies."

4. Figure Mistypes:
We have reviewed and corrected all typographical errors in Figure 1 to ensure clarity and consistency.

We hope these revisions adequately address your concerns and improve the overall quality of the manuscript.

Regards 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript "Ketamine and Esketamine in Psychiatry: A Comparative Re-2 view Emphasizing Neuroplasticity and Clinical Applications" by Mikellides presents a narrative review of the pharmacology, mechanisms of action, clinical efficacy, and safety profiles of Esketamine and Ketamine. The author also provides some regulatory considerations.

 

The manuscript is well-structured, and the writing is clear, aiding readers' comprehension.

Treatment of resistant depression with esketamine and ketamine is currently a highly relevant topic in psychiatric practice, as it is becoming a trend. Thus, the benefits and issues of its use are undoubtedly insightful. The sections "Psychotherapeutic Integration and Emerging Paradigms" show critical thinking and awareness of the psycho-spiritual dimension of ketamine therapy. Moreover, the paper appropriately addresses future directions and clinical implications.

 

Concerns

As a narrative review, it lacks a section describing the search strategy, inclusion and exclusion criteria, and databases used. The author should provide a brief methods paragraph to clarify how sources were selected.

 

While the paper summarises the evidence well, its limitations, biases in clinical trials, or controversies are not addressed. The author should briefly highlight the limitations of key studies and ongoing controversies.

Author Response

Thank you for your review, we have done changes which also includes:

This review is based on a narrative synthesis of peer-reviewed literature. Relevant publications were identified through PubMed, Scopus, and Google Scholar using keywords such as ‘ketamine’, ‘esketamine’, ‘neuroplasticity’, ‘treatment-resistant depression’, and ‘NMDA antagonists’. Studies were included if they were original research articles, meta-analyses, or systematic reviews published in English between 2000 and 2024. Priority was given to high-impact clinical trials and mechanistic studies. Editorials, non-peer-reviewed articles, and preprints were excluded.”

In response to your suggestion, we have also added a paragraph, this paragraph reads:

“Despite promising findings, the current evidence base for ketamine and esketamine contains several limitations. Many clinical trials have small sample sizes, short follow-up periods, and variations in dosing protocols, making comparisons difficult. Additionally, concerns persist regarding long-term safety, potential for misuse, and the interpretive challenges of dissociation as a therapeutic mechanism. These limitations underscore the need for cautious clinical implementation and ongoing research.”

Regards 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for corrections. In my opinion the manuscript is now ready for publication