Anesthetic Considerations for Patients on Psychotropic Drug Therapies

Round 1

Reviewer 1 Report

This is a very interesting paper summarizing evidence on the anesthesic considerations when treating patients under treatment with psychotropic medications. The paper is of quality and I would recommend it to be published. However, before the publication, I suggest some minor changes.

The introduction is clear and represents a good presentation of the objectives of the paper. However, Methods section is lacking. I would recommend to add two paragraphs explaining how the authors have conducted the review. Which sources have they searched? Which search terms they used?

In the third paragraph of the Tricyclic antidepressants section, the authors reported that TCAs lowe the siezure threshold and meperidine should be avoided. I recommend to add a reference to justify this recommendation.

In the third paragraph of the SSRIs and SNRIs section, it is stated that these drugs can result in abnormal bleeding secondary to alterations of platelet serotonin levels. Why? Which is the mechanism? A brief explanation is recommended.

On the section about "Other Antidepressants", the authors reported that mirtazapine has antihistamine effects which are highly associated with its sedative compounds. However, these sedative effects are depending on the dose. Paradoxically, lower doses seem to be more sedative than higher. I consider these should be added in the manuscript with one more reference.

In the fourth paragraph of the Antipsychotics section, the authors report that paliperidone is primarily excreted via the kidneys and not extensively metabolized by hepatic enzymes. "This small fraction inactivated by hepatic enzymes", through which enzymes is metabolized?

In the subsection about "Mood stabilizers", the authors describe interactions with lithium, valproic acid, carbamazepine and lamotrigine. What about oxcarbamazepine? I would recommend to add some words about it.

In the second paragraph about "Benzodiazepines", the authors mentioned that premedication with benzodiazepines is associated with higher risk of post-operative delirium. Which is the frequency of such association?

At the end of the paper the authors present a section called "Summary". I would prefer to called it "Discussion and conclusions". Furthermore, I recommend to extend this part. Three or four more paragraphs are expected.

Table 1 , 2 and 3 are first mentioned at the end of the manuscript. I would intergrate them before.

Author Response

Thank you for your comments and for the opportunity to revise our manuscript. Our responses are the bulleted points below.

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This is a very interesting paper summarizing evidence on the anesthesic considerations when treating patients under treatment with psychotropic medications. The paper is of quality and I would recommend it to be published. However, before the publication, I suggest some minor changes.

The introduction is clear and represents a good presentation of the objectives of the paper. However, Methods section is lacking. I would recommend to add two paragraphs explaining how the authors have conducted the review. Which sources have they searched? Which search terms they used?

• Thank you for this suggestion. We have added a Methods section explaining how the review was conducted.

In the third paragraph of the Tricyclic antidepressants section, the authors reported that TCAs lowe the siezure threshold and meperidine should be avoided. I recommend to add a reference to justify this recommendation.

• Thank you for this suggestion. The reference has been added accordingly.

In the third paragraph of the SSRIs and SNRIs section, it is stated that these drugs can result in abnormal bleeding secondary to alterations of platelet serotonin levels. Why? Which is the mechanism? A brief explanation is recommended.

• Thank you for your recommendation—the proposed mechanisms of increased bleeding risk with SSRIs and SNRIs have been added.

On the section about "Other Antidepressants", the authors reported that mirtazapine has antihistamine effects which are highly associated with its sedative compounds. However, these sedative effects are depending on the dose. Paradoxically, lower doses seem to be more sedative than higher. I consider these should be added in the manuscript with one more reference.

• Thank you for the suggestion. A reference has been added to explain this phenomenon.

In the fourth paragraph of the Antipsychotics section, the authors report that paliperidone is primarily excreted via the kidneys and not extensively metabolized by hepatic enzymes. "This small fraction inactivated by hepatic enzymes", through which enzymes is metabolized?

• The enzymes implicated in the metabolism have been added to the text.

 “Cytochrome P450 CYP3A4 and CYP2D6 enzymes have been implicated in the metabolism of paliperidone.”

In the subsection about "Mood stabilizers", the authors describe interactions with lithium, valproic acid, carbamazepine and lamotrigine. What about oxcarbamazepine? I would recommend to add some words about it.

• Thank you for the suggestion. We included oxcarbamazepine to the mood stabliizers section and discussed potential interaction and if usage should be continued in the perioperative period.

In the second paragraph about "Benzodiazepines", the authors mentioned that premedication with benzodiazepines is associated with higher risk of post-operative delirium. Which is the frequency of such association?

• Premedication with benzodiazepines preoperatively is associated with a higher incidence of post-operative delirium (odds ratio of 3.0) with a dose dependent relationship (each mg of midazolam administered is associated with an increased risk of postoperative delirium of up to 8%) This has been added to the manuscript.

At the end of the paper the authors present a section called "Summary". I would prefer to called it "Discussion and conclusions". Furthermore, I recommend to extend this part. Three or four more paragraphs are expected.

• Thank you for this suggestion. We have revised this section accordingly.

Table 1 , 2 and 3 are first mentioned at the end of the manuscript. I would intergrate them before.

• Thanks for this suggestion. These are referenced earlier in the manuscript.

Reviewer 2 Report

Thank you for permitting me to review this manuscript 

Introduction Line 6

Please provide reference (PPR) for elderly  

Is lithium dosage necessary before anesthesia ?  may bez this can be added to the text

 IMAO / intraoperatively blood pressure should be  monitored carefully ....

This is not very helpfull , as blood pressure is continuously monitored it should choose betwwen invasive or non invasive blood pressure monitoring 

Side efffects of MAOI are results of changes in neurotransmitter concentrations   (PPR )

Phenelzine has been shown to decrease plasma cholinesterase and can therefore prolong neuromuscular blockade with succinylcholine [6]

(Please add mivacurium as it is also eliminated with plasma cholinesterase 

For herbal supplements a short clinical guideline shouls be stated and may be inclusion in the tables  stating simply pay attention is not enough in my point of view would be any withdrawal syndrome if they are discontinued ? 

Please detail in reference (include) clinical anesthesiology Ch 28

Caution should be taken when administering bolus doses of barbiturates in situations where the baroreceptor response may be blunted or absent, such as in hypovolemia, cardiac tamponade, beta-adrenergic blockade, and congestive heart failure (cervical radiotherapy also afect baroreceptor response , this can also be added )

Author Response

Thank you for reviewing our manuscript and for the opportunity to submit a revision. Our responses are included below as bullet points.

Introduction Line 6

Please provide reference (PPR) for elderly  

• Thanks for this suggestion. We have added this citation.

Is lithium dosage necessary before anesthesia ?  may bez this can be added to the text

• Thank you for the comment. We included dosage of lithium that patients are usually on. We also had a sentence that recommended stopping lithium 72hours prior to surgery.

 IMAO / intraoperatively blood pressure should be  monitored carefully ....

This is not very helpfull , as blood pressure is continuously monitored it should choose betwwen invasive or non invasive blood pressure monitoring 

• Thank you for the suggestion. The following has been added: “Intraoperatively, blood pressure should be monitored carefully given the risk of orthostatic hypotension and hypertensive crisis with an exaggerated response to sympathomimetics. The placement of an arterial line can be considered for patients with other comorbidities (eg cardiac) at the discretion of the anesthesiologist.”

Side efffects of MAOI are results of changes in neurotransmitter concentrations   (PPR )

• Thank you, a reference has been added.

Phenelzine has been shown to decrease plasma cholinesterase and can therefore prolong neuromuscular blockade with succinylcholine [6] (Please add mivacurium as it is also eliminated with plasma cholinesterase

• Thank you for the great suggestion, this has been added.

For herbal supplements a short clinical guideline shouls be stated and may be inclusion in the tables  stating simply pay attention is not enough in my point of view would be any withdrawal syndrome if they are discontinued ? 

• Thank you for the recommendation. Additional information has been added regarding herbal supplementation, with the addition to the table.

Please detail in reference (include) clinical anesthesiology Ch 28

• Thank you for the suggestion. We included the reference for clinical anesthesiology into our reference list.

Caution should be taken when administering bolus doses of barbiturates in situations where the baroreceptor response may be blunted or absent, such as in hypovolemia, cardiac tamponade, beta-adrenergic blockade, and congestive heart failure (cervical radiotherapy also afect baroreceptor response , this can also be added )

• Thank you for this suggestion. This has been added to the revision.