Title: Comorbid Psychiatric Disorders and Long-Term Survival after Liver Transplantation in
Transplant Facilities with a Psychiatric Consultation-Liaison Team: a Multicenter Retrospective
Study
Version: 1 Date: 29 Nov 2022
Reviewer's report:
This is a retrospective, non-randomized, observational study report with the title “Comorbid
Psychiatric Disorders and Long-Term Survival after Liver Transplantation in Transplant
Facilities with a Psychiatric Consultation-Liaison Team: a Multicenter Retrospective Study”.
The author had published a similar retrospective observational report with the title “Risk factors
and long-term outcomes of living donors of liver transplantation with postoperative psychiatric
complications”. The study target was changed from donors to recipients.
This study could not assist decision making for potential liver recipients with major psychiatric
disorder except delirium during pre-transplantation psychiatric evaluation and health education.
All liver recipients might encounter psychiatric problems after liver transplantation similar to
other people after major surgery. This manuscript does not show new novelty because comorbid
psychiatric disorders do not affect survival of liver transplant recipients.
The reviewer had the following questions for this manuscript:
1. The reviewer could recognize the difficulty to collect enough transplantation recipients with
psychiatric diagnosis and mortality related to psychiatric problems. If so, the authors might
include more cases from more hospitals. Does the pre-transplant evaluation have consensus
before this study?  All hospitals did not offer schedule-based follow-up protocol annually as
donors in previous study.
2. Could the authors compare the similarities or different aspects of the selected eight institutions
(Hokkaido University, Jichi University, Keio University, Tokyo Women's Medical University,
Nagoya University, Kyoto University, Okayama University, and Kyushu University) for their
transplant program (pretransplant evaluation policy, post-transplant follow-up frequency, health
check-up charge, treatment strategy)? Is the transplant care quality (transplant team manpower,
qualification, resource…etc) and psychiatric monitoring policy of these eight hospitals similar
enough that the patients’ outcomes could be put together for analysis?
3. How did the authors categorize the recipients with comorbid psychiatric disorders (comorbid
psychiatric disorders group: CP group)? The clinical course and impact to transplant course
of the CP group are totally different, regarding insomnia, delirium, major depressive disorder,
adjustment disorder, anxiety disorder, intellectual disability, autism spectrum disorder, somatic
symptom disorder, schizophrenia, substance use disorder and personality disorder. Delirium is
a short-term and curable disorder; however, schizophrenia and major depressive disorder had
more long-term course with life mortality rate around 15%. Intellectual disability and autism
spectrum disorder had long-term course with various impact to transplant course according to the
patients’ function and families’ care quality. Substance use disorder and personality disorder had
more various presentation with unexpected course. Insomnia, adjustment disorder, and anxiety
disorder should not be categorized as comorbid psychiatric disorders with the aforementioned
disorders as it may be related to physical or medication condition. Only major active psychiatric
disorders should be of significance for study. How could these various patients be categorized
in the same group for analysis of mortality?
4. It is common knowledge that delirium is related to mortality post transplantation. Delirium is
related to older age, severe physical illness, and resultant long hospitalized days. It is better that
comorbid psychiatric disorders exclude delirium in general, and not only within 1 week after
transplant in table 3, as delirium after that initial first week after transplant can also be associated
to physical or medical condition rather than psychiatric disorder. These patients with delirium
should be another study group because delirium has a different illness course. Delirium before
and short-time after transplant could be regarded as complication of illness, transplantation
surgery or medication that should be classified as another group or excluded from this study.
5. Could authors analyse transplantation outcome (complication and mortality) of the different
patient groups with comorbid major psychiatric disorders (schizophrenia, major depressive
disorder, mild intellectual disability, and autism spectrum disorder), comorbid minor psychiatric
disorders (insomnia, adjustment disorder, and anxiety disorder) and other psychiatric disorders
(substance use disorder and personality disorder) by one year, and three year? The category of
over 3 years may not have clinical significance as too many confounding factors could occur
in this duration.
6. There are many factors related to severe complication or mortality after transplantation.
The authors confirmed age and hospitalization days in Table 4 as two of these factors. The
patients with major depressive disorder got hazard ratio of 2.66 with significant level in spite of
referral to psychiatrists in Table 3. It is important to analyse the major death causes related to
major depressive disorder diagnosis, before or after transplantation, such as suicide, non-medical
adherence to immunosuppressants, poor personal care, accident prone behavior by underlying
psychiatric disorder, inadequate support by psychiatric problems…etc.
7. The time of diagnosis of comorbid psychiatric disorder and relationship to transplant surgery
should be clarified. The authors compared the groups including delirium, insomnia, major
depressive disorder with the group not including comorbid psychiatric disorders to calculate the
hazard ratio of the survival rate for each comorbid psychiatric disorder irrespective of different
times of diagnosis of psychiatric disorders in Table 3. However, the groups including delirium,
insomnia, major depressive disorder consisted of different times of diagnosis of psychiatric
disorders. There are different clinical implications to survival rate in respect to different times of
diagnosis of psychiatric disorders. For example, mortality cases with newly diagnosed insomnia
and major depressive disorder near to the time of transplant might be related to physical problems
compared to those diagnosed at a later period.
8. The authors mentioned “As per the transplantation criteria in Japan, recipient candidates
with liver cirrhosis owing to alcohol use disorders were disqualified from transplant listing if
they had not been abstinent for the last 6 months (on February 20, 2014, this changed to 18
months).”  However, many alcoholic patients’ severe physical condition from liver failure could
not allow patients to get a new life after a abstinence period of 6~18 months. This criterion
deprives alcoholic patients with severe condition to get liver transplantation in time. How many
of 21 patients with substance use disorder met alcohol or substance abstinence criterion in Table
2? Did all patients with newly diagnosed substance use disorder in 3 months to 3 year meet
this criterion? Did these patients conceal their abstinence period to the expert psychiatrists and
psychologists during pre-transplantation evaluation? What is the relevance of mentioning the
abstinence criteria?
9. It is difficult to record multiple comorbidities after transplantation. The expert psychiatrists
and psychologists did not evaluate the patients on schedule-based period after transplantation.
The authors did not analyse the detailed characteristics of newly diagnosed psychiatric
patients after transplantation. Are these new diagnoses of psychiatric disorders related to pre-
transplantation psychiatric diagnoses or newly incidental psychiatric disorder?
10. The authors investigated the prevalence of comorbid psychiatric disorders in liver transplant
recipients, and whether both overall and specific psychiatric comorbidities affected their long-
term survival. However, the patients with severe comorbid major psychiatric disorders might be
excluded after pre-transplantation psychiatric evaluations. Therefore, patients with more minor
psychiatric disorders resulted in the conclusion that comorbid psychiatric disorders did not
affect survival of liver transplant recipients. This conclusion might be influenced by selection
bias, no appropriate monitoring, referral expert psychiatrists and difference in care by different
liver transplantation team staffs. Analysis for treatment course of difficult cases with pre-
transplantation major psychiatric disorder would be more interesting to readers.
11. It is better if the authors matched these two groups (comorbid major psychiatric diagnosis
without delirium and others without delirium) at pretransplant evaluation with comparable
follow-up time and health condition in a defined period. Comparison of mortality and
postoperative psychiatric complications with similar follow-up times and health conditions
could have clinical implication for potential transplant recipient.
12. It is better to have over 30 cases in each group for comparison, otherwise, the results of
statistics is hard to be interpreted! These unreasonable outcomes come from too few cases of
liver recipients with major psychiatric diagnoses (excluding delirium) before transplantation.
13. Some spelling errors in Tablekimura.docx need to be corrected as following:
Table 1 No Comorbided Psychiatric disorders Group -> No Comorbid Psychiatric disorders
Group
Table2.  Time of diagnosis of psychiatric disorderss -> Table 2. Time of diagnosis of psychiatric
disorders
In Table 2 line 9, intellecutual disability -> intellectual disability
In Table 3, Table 4, Table 5, Table 6    all “cormorbid” -> “comorbid”
In Table 6 “MELD,Model foe end-stage liver disease” -> “MELD, Model for end-stage liver
disease”
In Table1, Table2, Table3, Table4, Table5, Table6 -> Table 1, Table 2, Table 3, Table 4, Table
5, Table 6
Title: Comorbid Psychiatric Disorders and Long-Term Survival after Liver Transplantation in
Transplant Facilities with a Psychiatric Consultation-Liaison Team: a Multicenter Retrospective
Study
Version: 1 Date: 29 Nov 2022
Reviewer's report:
This is a retrospective, non-randomized, observational study report with the title “Comorbid
Psychiatric Disorders and Long-Term Survival after Liver Transplantation in Transplant
Facilities with a Psychiatric Consultation-Liaison Team: a Multicenter Retrospective Study”.
The author had published a similar retrospective observational report with the title “Risk factors
and long-term outcomes of living donors of liver transplantation with postoperative psychiatric
complications”. The study target was changed from donors to recipients.
This study could not assist decision making for potential liver recipients with major psychiatric
disorder except delirium during pre-transplantation psychiatric evaluation and health education.
All liver recipients might encounter psychiatric problems after liver transplantation similar to
other people after major surgery. This manuscript does not show new novelty because comorbid
psychiatric disorders do not affect survival of liver transplant recipients.
The reviewer had the following questions for this manuscript:
1. The reviewer could recognize the difficulty to collect enough transplantation recipients with
psychiatric diagnosis and mortality related to psychiatric problems. If so, the authors might
include more cases from more hospitals. Does the pre-transplant evaluation have consensus
before this study?  All hospitals did not offer schedule-based follow-up protocol annually as
donors in previous study.
2. Could the authors compare the similarities or different aspects of the selected eight institutions
(Hokkaido University, Jichi University, Keio University, Tokyo Women's Medical University,
Nagoya University, Kyoto University, Okayama University, and Kyushu University) for their
transplant program (pretransplant evaluation policy, post-transplant follow-up frequency, health
check-up charge, treatment strategy)? Is the transplant care quality (transplant team manpower,
qualification, resource…etc) and psychiatric monitoring policy of these eight hospitals similar
enough that the patients’ outcomes could be put together for analysis?
3. How did the authors categorize the recipients with comorbid psychiatric disorders (comorbid
psychiatric disorders group: CP group)? The clinical course and impact to transplant course
of the CP group are totally different, regarding insomnia, delirium, major depressive disorder,
adjustment disorder, anxiety disorder, intellectual disability, autism spectrum disorder, somatic
symptom disorder, schizophrenia, substance use disorder and personality disorder. Delirium is
a short-term and curable disorder; however, schizophrenia and major depressive disorder had
more long-term course with life mortality rate around 15%. Intellectual disability and autism
spectrum disorder had long-term course with various impact to transplant course according to the
patients’ function and families’ care quality. Substance use disorder and personality disorder had
more various presentation with unexpected course. Insomnia, adjustment disorder, and anxiety
disorder should not be categorized as comorbid psychiatric disorders with the aforementioned
disorders as it may be related to physical or medication condition. Only major active psychiatric
disorders should be of significance for study. How could these various patients be categorized
in the same group for analysis of mortality?
4. It is common knowledge that delirium is related to mortality post transplantation. Delirium is
related to older age, severe physical illness, and resultant long hospitalized days. It is better that
comorbid psychiatric disorders exclude delirium in general, and not only within 1 week after
transplant in table 3, as delirium after that initial first week after transplant can also be associated
to physical or medical condition rather than psychiatric disorder. These patients with delirium
should be another study group because delirium has a different illness course. Delirium before
and short-time after transplant could be regarded as complication of illness, transplantation
surgery or medication that should be classified as another group or excluded from this study.
5. Could authors analyse transplantation outcome (complication and mortality) of the different
patient groups with comorbid major psychiatric disorders (schizophrenia, major depressive
disorder, mild intellectual disability, and autism spectrum disorder), comorbid minor psychiatric
disorders (insomnia, adjustment disorder, and anxiety disorder) and other psychiatric disorders
(substance use disorder and personality disorder) by one year, and three year? The category of
over 3 years may not have clinical significance as too many confounding factors could occur
in this duration.
6. There are many factors related to severe complication or mortality after transplantation.
The authors confirmed age and hospitalization days in Table 4 as two of these factors. The
patients with major depressive disorder got hazard ratio of 2.66 with significant level in spite of
referral to psychiatrists in Table 3. It is important to analyse the major death causes related to
major depressive disorder diagnosis, before or after transplantation, such as suicide, non-medical
adherence to immunosuppressants, poor personal care, accident prone behavior by underlying
psychiatric disorder, inadequate support by psychiatric problems…etc.
7. The time of diagnosis of comorbid psychiatric disorder and relationship to transplant surgery
should be clarified. The authors compared the groups including delirium, insomnia, major
depressive disorder with the group not including comorbid psychiatric disorders to calculate the
hazard ratio of the survival rate for each comorbid psychiatric disorder irrespective of different
times of diagnosis of psychiatric disorders in Table 3. However, the groups including delirium,
insomnia, major depressive disorder consisted of different times of diagnosis of psychiatric
disorders. There are different clinical implications to survival rate in respect to different times of
diagnosis of psychiatric disorders. For example, mortality cases with newly diagnosed insomnia
and major depressive disorder near to the time of transplant might be related to physical problems
compared to those diagnosed at a later period.
8. The authors mentioned “As per the transplantation criteria in Japan, recipient candidates
with liver cirrhosis owing to alcohol use disorders were disqualified from transplant listing if
they had not been abstinent for the last 6 months (on February 20, 2014, this changed to 18
months).”  However, many alcoholic patients’ severe physical condition from liver failure could
not allow patients to get a new life after a abstinence period of 6~18 months. This criterion
deprives alcoholic patients with severe condition to get liver transplantation in time. How many
of 21 patients with substance use disorder met alcohol or substance abstinence criterion in Table
2? Did all patients with newly diagnosed substance use disorder in 3 months to 3 year meet
this criterion? Did these patients conceal their abstinence period to the expert psychiatrists and
psychologists during pre-transplantation evaluation? What is the relevance of mentioning the
abstinence criteria?
9. It is difficult to record multiple comorbidities after transplantation. The expert psychiatrists
and psychologists did not evaluate the patients on schedule-based period after transplantation.
The authors did not analyse the detailed characteristics of newly diagnosed psychiatric
patients after transplantation. Are these new diagnoses of psychiatric disorders related to pre-
transplantation psychiatric diagnoses or newly incidental psychiatric disorder?
10. The authors investigated the prevalence of comorbid psychiatric disorders in liver transplant
recipients, and whether both overall and specific psychiatric comorbidities affected their long-
term survival. However, the patients with severe comorbid major psychiatric disorders might be
excluded after pre-transplantation psychiatric evaluations. Therefore, patients with more minor
psychiatric disorders resulted in the conclusion that comorbid psychiatric disorders did not
affect survival of liver transplant recipients. This conclusion might be influenced by selection
bias, no appropriate monitoring, referral expert psychiatrists and difference in care by different
liver transplantation team staffs. Analysis for treatment course of difficult cases with pre-
transplantation major psychiatric disorder would be more interesting to readers.
11. It is better if the authors matched these two groups (comorbid major psychiatric diagnosis
without delirium and others without delirium) at pretransplant evaluation with comparable
follow-up time and health condition in a defined period. Comparison of mortality and
postoperative psychiatric complications with similar follow-up times and health conditions
could have clinical implication for potential transplant recipient.
12. It is better to have over 30 cases in each group for comparison, otherwise, the results of
statistics is hard to be interpreted! These unreasonable outcomes come from too few cases of
liver recipients with major psychiatric diagnoses (excluding delirium) before transplantation.
13. Some spelling errors in Tablekimura.docx need to be corrected as following:
Table 1 No Comorbided Psychiatric disorders Group -> No Comorbid Psychiatric disorders
Group
Table2.  Time of diagnosis of psychiatric disorderss -> Table 2. Time of diagnosis of psychiatric
disorders
In Table 2 line 9, intellecutual disability -> intellectual disability
In Table 3, Table 4, Table 5, Table 6    all “cormorbid” -> “comorbid”
In Table 6 “MELD,Model foe end-stage liver disease” -> “MELD, Model for end-stage liver
disease”
In Table1, Table2, Table3, Table4, Table5, Table6 -> Table 1, Table 2, Table 3, Table 4, Table
5, Table 6
Please review this paper.
user
Title: Comorbid Psychiatric Disorders and Long-Term Survival after Liver Transplantation in
Transplant Facilities with a Psychiatric Consultation-Liaison Team: a Multicenter Retrospective
Study
Version: 1 Date: 29 Nov 2022
Reviewer's report:
This is a retrospective, non-randomized, observational study report with the title “Comorbid
Psychiatric Disorders and Long-Term Survival after Liver Transplantation in Transplant
Facilities with a Psychiatric Consultation-Liaison Team: a Multicenter Retrospective Study”.
The author had published a similar retrospective observational report with the title “Risk factors
and long-term outcomes of living donors of liver transplantation with postoperative psychiatric
complications”. The study target was changed from donors to recipients.
This study could not assist decision making for potential liver recipients with major psychiatric
disorder except delirium during pre-transplantation psychiatric evaluation and health education.
All liver recipients might encounter psychiatric problems after liver transplantation similar to
other people after major surgery. This manuscript does not show new novelty because comorbid
psychiatric disorders do not affect survival of liver transplant recipients.
The reviewer had the following questions for this manuscript:
1. The reviewer could recognize the difficulty to collect enough transplantation recipients with
psychiatric diagnosis and mortality related to psychiatric problems. If so, the authors might
include more cases from more hospitals. Does the pre-transplant evaluation have consensus
before this study?  All hospitals did not offer schedule-based follow-up protocol annually as
donors in previous study.
2. Could the authors compare the similarities or different aspects of the selected eight institutions
(Hokkaido University, Jichi University, Keio University, Tokyo Women's Medical University,
Nagoya University, Kyoto University, Okayama University, and Kyushu University) for their
transplant program (pretransplant evaluation policy, post-transplant follow-up frequency, health
check-up charge, treatment strategy)? Is the transplant care quality (transplant team manpower,
qualification, resource…etc) and psychiatric monitoring policy of these eight hospitals similar
enough that the patients’ outcomes could be put together for analysis?
3. How did the authors categorize the recipients with comorbid psychiatric disorders (comorbid
psychiatric disorders group: CP group)? The clinical course and impact to transplant course
of the CP group are totally different, regarding insomnia, delirium, major depressive disorder,
adjustment disorder, anxiety disorder, intellectual disability, autism spectrum disorder, somatic
symptom disorder, schizophrenia, substance use disorder and personality disorder. Delirium is
a short-term and curable disorder; however, schizophrenia and major depressive disorder had
more long-term course with life mortality rate around 15%. Intellectual disability and autism
spectrum disorder had long-term course with various impact to transplant course according to the
patients’ function and families’ care quality. Substance use disorder and personality disorder had
more various presentation with unexpected course. Insomnia, adjustment disorder, and anxiety
disorder should not be categorized as comorbid psychiatric disorders with the aforementioned
disorders as it may be related to physical or medication condition. Only major active psychiatric
disorders should be of significance for study. How could these various patients be categorized
in the same group for analysis of mortality?
4. It is common knowledge that delirium is related to mortality post transplantation. Delirium is
related to older age, severe physical illness, and resultant long hospitalized days. It is better that
comorbid psychiatric disorders exclude delirium in general, and not only within 1 week after
transplant in table 3, as delirium after that initial first week after transplant can also be associated
to physical or medical condition rather than psychiatric disorder. These patients with delirium
should be another study group because delirium has a different illness course. Delirium before
and short-time after transplant could be regarded as complication of illness, transplantation
surgery or medication that should be classified as another group or excluded from this study.
5. Could authors analyse transplantation outcome (complication and mortality) of the different
patient groups with comorbid major psychiatric disorders (schizophrenia, major depressive
disorder, mild intellectual disability, and autism spectrum disorder), comorbid minor psychiatric
disorders (insomnia, adjustment disorder, and anxiety disorder) and other psychiatric disorders
(substance use disorder and personality disorder) by one year, and three year? The category of
over 3 years may not have clinical significance as too many confounding factors could occur
in this duration.
6. There are many factors related to severe complication or mortality after transplantation.
The authors confirmed age and hospitalization days in Table 4 as two of these factors. The
patients with major depressive disorder got hazard ratio of 2.66 with significant level in spite of
referral to psychiatrists in Table 3. It is important to analyse the major death causes related to
major depressive disorder diagnosis, before or after transplantation, such as suicide, non-medical
adherence to immunosuppressants, poor personal care, accident prone behavior by underlying
psychiatric disorder, inadequate support by psychiatric problems…etc.
7. The time of diagnosis of comorbid psychiatric disorder and relationship to transplant surgery
should be clarified. The authors compared the groups including delirium, insomnia, major
depressive disorder with the group not including comorbid psychiatric disorders to calculate the
hazard ratio of the survival rate for each comorbid psychiatric disorder irrespective of different
times of diagnosis of psychiatric disorders in Table 3. However, the groups including delirium,
insomnia, major depressive disorder consisted of different times of diagnosis of psychiatric
disorders. There are different clinical implications to survival rate in respect to different times of
diagnosis of psychiatric disorders. For example, mortality cases with newly diagnosed insomnia
and major depressive disorder near to the time of transplant might be related to physical problems
compared to those diagnosed at a later period.
8. The authors mentioned “As per the transplantation criteria in Japan, recipient candidates
with liver cirrhosis owing to alcohol use disorders were disqualified from transplant listing if
they had not been abstinent for the last 6 months (on February 20, 2014, this changed to 18
months).”  However, many alcoholic patients’ severe physical condition from liver failure could
not allow patients to get a new life after a abstinence period of 6~18 months. This criterion
deprives alcoholic patients with severe condition to get liver transplantation in time. How many
of 21 patients with substance use disorder met alcohol or substance abstinence criterion in Table
2? Did all patients with newly diagnosed substance use disorder in 3 months to 3 year meet
this criterion? Did these patients conceal their abstinence period to the expert psychiatrists and
psychologists during pre-transplantation evaluation? What is the relevance of mentioning the
abstinence criteria?
9. It is difficult to record multiple comorbidities after transplantation. The expert psychiatrists
and psychologists did not evaluate the patients on schedule-based period after transplantation.
The authors did not analyse the detailed characteristics of newly diagnosed psychiatric
patients after transplantation. Are these new diagnoses of psychiatric disorders related to pre-
transplantation psychiatric diagnoses or newly incidental psychiatric disorder?
10. The authors investigated the prevalence of comorbid psychiatric disorders in liver transplant
recipients, and whether both overall and specific psychiatric comorbidities affected their long-
term survival. However, the patients with severe comorbid major psychiatric disorders might be
excluded after pre-transplantation psychiatric evaluations. Therefore, patients with more minor
psychiatric disorders resulted in the conclusion that comorbid psychiatric disorders did not
affect survival of liver transplant recipients. This conclusion might be influenced by selection
bias, no appropriate monitoring, referral expert psychiatrists and difference in care by different
liver transplantation team staffs. Analysis for treatment course of difficult cases with pre-
transplantation major psychiatric disorder would be more interesting to readers.
11. It is better if the authors matched these two groups (comorbid major psychiatric diagnosis
without delirium and others without delirium) at pretransplant evaluation with comparable
follow-up time and health condition in a defined period. Comparison of mortality and
postoperative psychiatric complications with similar follow-up times and health conditions
could have clinical implication for potential transplant recipient.
12. It is better to have over 30 cases in each group for comparison, otherwise, the results of
statistics is hard to be interpreted! These unreasonable outcomes come from too few cases of
liver recipients with major psychiatric diagnoses (excluding delirium) before transplantation.
13. Some spelling errors in Tablekimura.docx need to be corrected as following:
Table 1 No Comorbided Psychiatric disorders Group -> No Comorbid Psychiatric disorders
Group
Table2.  Time of diagnosis of psychiatric disorderss -> Table 2. Time of diagnosis of psychiatric
disorders
In Table 2 line 9, intellecutual disability -> intellectual disability
In Table 3, Table 4, Table 5, Table 6    all “cormorbid” -> “comorbid”
In Table 6 “MELD,Model foe end-stage liver disease” -> “MELD, Model for end-stage liver
disease”
In Table1, Table2, Table3, Table4, Table5, Table6 -> Table 1, Table 2, Table 3, Table 4, Table
5, Table 6
assistant