The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease

Round 1

Reviewer 1 Report

General comment:

This is an important review article. The authors review the current evidence about the efficacy of ketamine in Alzheimer’s disease (AD) management. I had some major concerns to be addressed before further consideration.

 

1. In the abstract, the authors started with “Depression is a leading cause of disability globally”. I agreed that depression is a major disease in the world. However, the authors then linked the depression to AD and said “There is evidence that depression is linked to certain neurodegenerative diseases, one being Alzheimer’s disease (AD). The efficacy of conventional antidepressants to treat AD is conflicting, especially regarding selective serotonin reuptake inhibitors (SSRIs).” I am not sure the rationale of this linkage. In my recognition, the main topic is ketamine in AD but not ketamine in Depression. In the view of psychiatry, depression is much different from AD.
2. In addition, the statement “The efficacy of conventional antidepressants to treat AD is conflicting, especially regarding selective serotonin reuptake inhibitors (SSRIs)” is unclear to me. The SSRI is initially designed to treat depression but not to AD. What symptoms of AD did the authors mean SSRI is not effective for?
3. The authors said “Ketamine, a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist, can be used to treat depression (7). A single sub-anesthetic dose of ketamine can be an alternative to electroconvulsive therapy in treatment-resistant depression (TRD) given its rapid action (8).” This statement is good. However, the authors should also mentioned the beneficial effect of add-on ketamine (not only a alternative choice) in the anesthesia in electroconvulsive therapy in depressive patients (PMID: 27908572).
4. In addition, the authors addressed about the adverse impact on the cognition by ketamine and said “The unclear role regarding the use of ketamine as a potential therapy for AD is due to ketamine’s side effects of dissociation, memory loss, confusion, and likelihood of abuse.” I generally agree with this statement. However, the ketamine (in the form of combined ketamine/midazolam) could exert a good effect to avoid some delirium-like behavior, such as pediatric emergency delirium (PMID: 34481361). Please briefly address this issue.
5. Further, the authors noticed that NMDA-blocker would have an adverse impact on the cognition. The authors should cite some reference to support the association between NMDA acting agents and changes of cognition. For example, the NMDA-enhancing agents may benefit young patients with schizophrenia (PMID: 30730250).
6. The authors said “Other presentations of AD can be olfactory dysfunction and sleep disturbances.” This statement is good. However, the association between AD and sleep disturbances is bidirectional and multifactorial. First, sleep disturbance will increase risk of AD and vice versa (PMID: 33745437). Second, the pharmacy managing cognitive function in AD would have unwanted impact on the sleep parameters (PMID: 34753629). To manage AD patients’ sleep could modify their cognition (PMID: 33957167). Please briefly address this issue.
7. At present time, the most evidences addressing effectiveness of ketamine on depression in AD patients were seldom. This might reflect a fact that the diagnosis of depression in patients with AD was difficult. For example, the interview with AD patients might face a dilemma, confabulation. We could not make sure whether the statement from AD patients were true or not. In addition, it would be difficult to differentiate whether the depression-like symptoms is true depression or dementia medication related adverse event. The authors should address this issue in their manuscript.
8. Finally, since there are too few clinical trials addressing the ketamine effectiveness on depression in AD patients, the title of current review should be modified into a more conservative one.

Author Response

This is an important review article. The authors review the current evidence about the efficacy of ketamine in Alzheimer’s disease (AD) management. I had some major concerns to be addressed before further consideration.

 

1. In the abstract, the authors started with “Depression is a leading cause of disability globally”. I agreed that depression is a major disease in the world. However, the authors then linked the depression to AD and said “There is evidence that depression is linked to certain neurodegenerative diseases, one being Alzheimer’s disease (AD). The efficacy of conventional antidepressants to treat AD is conflicting, especially regarding selective serotonin reuptake inhibitors (SSRIs).” I am not sure the rationale of this linkage. In my recognition, the main topic is ketamine in AD but not ketamine in Depression. In the view of psychiatry, depression is much different from AD.

Answer: You are correct depression is much different from AD. However, the point is that depression in AD seems to be much more difficult to treat than depression alone. This has been seen in studies that use the gold standard of medical treatment like SSRIs and how it doesn’t really have the same effect in depression with AD is also present. That is what makes ketamine used in treating depression in the presence of AD is interesting. It has been seen in studies to be useful in treatment resistant depression so that is why researchers feel that it may help with depression that is co-morbid in other disease states such as AD. That is what that statement means and why it was linked together.

 

1. In addition, the statement “The efficacy of conventional antidepressants to treat AD is conflicting, especially regarding selective serotonin reuptake inhibitors (SSRIs)” is unclear to me. The SSRI is initially designed to treat depression but not to AD. What symptoms of AD did the authors mean SSRI is not effective for?

Answer: That statement is confusing. This has been amended in the revision as it was the depression we were talking about in the presence of AD.

 

1. The authors said “Ketamine, a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist, can be used to treat depression (7). A single sub-anesthetic dose of ketamine can be an alternative to electroconvulsive therapy in treatment-resistant depression (TRD) given its rapid action (8).” This statement is good. However, the authors should also mentioned the beneficial effect of add-on ketamine (not only a alternative choice) in the anesthesia in electroconvulsive therapy in depressive patients (PMID: 27908572).

 

Answer: This was mentioned as a study in the clinical studies section.

 

1. In addition, the authors addressed about the adverse impact on the cognition by ketamine and said “The unclear role regarding the use of ketamine as a potential therapy for AD is due to ketamine’s side effects of dissociation, memory loss, confusion, and likelihood of abuse.” I generally agree with this statement. However, the ketamine (in the form of combined ketamine/midazolam) could exert a good effect to avoid some delirium-like behavior, such as pediatric emergency delirium (PMID: 34481361). Please briefly address this issue.

 

Answer: We will decline putting this in because our focus isn’t in the pediatric population and with Midazolam it may have a paradoxical effect on the elderly population. It may actually worsen delirium in that population.

 

1. Further, the authors noticed that NMDA-blocker would have an adverse impact on the cognition. The authors should cite some reference to support the association between NMDA acting agents and changes of cognition. For example, the NMDA-enhancing agents may benefit young patients with schizophrenia (PMID: 30730250).

Answer: It is thought to help young patients but again that isn’t the purpose of this paper so we will leave this out to avoid confusion.

 

1. The authors said “Other presentations of AD can be olfactory dysfunction and sleep disturbances.” This statement is good. However, the association between AD and sleep disturbances is bidirectional and multifactorial. First, sleep disturbance will increase risk of AD and vice versa (PMID: 33745437). Second, the pharmacy managing cognitive function in AD would have unwanted impact on the sleep parameters (PMID: 34753629). To manage AD patients’ sleep could modify their cognition (PMID: 33957167). Please briefly address this issue.

Answer: We agree with addressing this issue. We added the second PMID. We decided to leave the first and third one out as we felt that this didn’t fit well with the manuscript.

 

1. At present time, the most evidences addressing effectiveness of ketamine on depression in AD patients were seldom. This might reflect a fact that the diagnosis of depression in patients with AD was difficult. For example, the interview with AD patients might face a dilemma, confabulation. We could not make sure whether the statement from AD patients were true or not. In addition, it would be difficult to differentiate whether the depression-like symptoms is true depression or dementia medication related adverse event. The authors should address this issue in their manuscript.

Answer: This was briefly addressed in the revision of this manuscript.

 

1. Finally, since there are too few clinical trials addressing the ketamine effectiveness on depression in AD patients, the title of current review should be modified into a more conservative one.

Answer: This is a great point. We have revised the title. We have also clarified it to make sure it was understood to the readers that it is for the use of depression in AD.

Reviewer 2 Report

Please consider two things in revision:

1) it needs to be made clear that there are no clinical data in Alzheimer's Disease patients per se - abstract and elsewhere

2) the ketamine literature is extensive - make it clear to the reader why you are summarizing the studies you summarize in the table and leaving others out please

Author Response

Please consider two things in revision:

• it needs to be made clear that there are no clinical data in Alzheimer's Disease patients per se - abstract and elsewhere

Answer: This is good point. This has been added to the manuscript. We also changed the title to reflect that it’s more of a possibility and instead of a clinical application.

 

• the ketamine literature is extensive - make it clear to the reader why you are summarizing the studies you summarize in the table and leaving others out please

Answer: Also a good point. We have added language in the studies section making this clear.

Reviewer 3 Report

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The biological changes caused by AD may intensify a predisposition to depression. On the other hand, depression may increase the chances of developing Alzheimer's disease. It's clear that depression has a strong effect on quality of life for people with Alzheimer's disease. Therefore, the manuscript submitted for review presents a current and clinically relevant problem. The manuscript is correctly structured in accordance with the requirements of scientific work.

The Authors describe the issues related to AD in an interesting and exhaustive way, including the characteristics of this disease and its current treatments, and the possibility of using ketamine in this therapy. In my opinion, the manuscript is very carefully and comprehensively compiled. My only suggestion is to change the title to e.g. „Clinical Application of Ketamine in the Treatment of Depression inc Alzheimer's Disease”. It should be emphasized that ketamine could be used in the treatment of depression observed in the course of AD.

 

Author Response

The Authors describe the issues related to AD in an interesting and exhaustive way, including the characteristics of this disease and its current treatments, and the possibility of using ketamine in this therapy. In my opinion, the manuscript is very carefully and comprehensively compiled. My only suggestion is to change the title to e.g. „Clinical Application of Ketamine in the Treatment of Depression inc Alzheimer's Disease”. It should be emphasized that ketamine could be used in the treatment of depression observed in the course of AD.

            Answer: Thank you for your time in reviewing our manuscript. This is a great point and the title has been changed in the revision

Round 2

Reviewer 1 Report

The authors had addressed the most of my comments. The current version is good to be accepted.

Reviewer 2 Report

thank you for the revision