Reviewer ’s report  
 
Title:  Hepatitis C virus eradication improves immediate and delayed episodic memory in 
patients treated with interferon and ribavirin  
 
Version: 0 Date: 21 Aug 2017 
 
Reviewer:  Renata  Fialho  
 
Reviewer’s report:  
 
The topic is very interesting and relevant to validate the interferon model of depression and to 
provide a better care. However this manuscript needs more work, and has great potential to 
provide interesting outcomes.    
 
 
 
Abstract: this sections would benefit from some rewriting to make it look neater. It might be 
worth it clarify the times points of assessment and exclusion criteria.  
 
Introduction: this section could benefit from a more comprehensive review about hepatitis C 
treatment, the authors developed an interesting background but is lacking the inflammatory 
model of Hepatitis C which is the core of neuropsychiatric side effects.  
 
Methods: TMT test the composite B -A is missing for analysis. the Part B performance is 
indicative of ability to flexibly shift the course of an ongoing task (shifting) (Kortte et al., 2002). 
It is a pen and pencil task consisting of two parts, A and B. In part A, the  participants have to 
connect the numbers 1 to 25 in ascending order. In part B, the participants should connect the 
numbers in an ascending order but with the added task of alternating between numbers and 
letters (i.e., 1 -A-2B) (Bowie & Harvey, 2006; Corr igan, 1987). A derived score  calculated by 
(B-A) reflects the unique task requirements of part B (Corrigan & Hinkeldey, 1987; Lamberty et 
al., 1994; Lezak, 1995; Misdraju & Gass, 2010), given crucial information about processing 
speed components.   
 
Resul ts: it seems that cognitive function impairment is associated with HCV replication and 
depression symptoms presentation shows differences before and after the treatment? If so the 
paper would benefit from analysis between these components, cognition and de pression. This 
section perhaps could benefit from some more data analysis. also, it could be relevant to clarify 
the time points of assessment because of their significant impact on CNS as described previously 
in the literature, in particular with greater impact on week 4.  
 
Discussion  
 
The main outcomes are very interesting but it needs a bit more work. It is a crucial topic that 
needs clarification. It is not clear what could explain the depression symptoms not being remitted 
and what are the potential in fluences on cognitive function. Probably it would benefit this section 
a more understanding paradigm of inflammatory model of neuropsychiatric side effects of 
interferon treatment.  
The sample size is also another issue that needs to be addressed accordingl y. 
 
for reference  
 
Fialho, R., Pereira, M., Harrison, N., Rusted, J., & Whale, R. (2017). Co -infection with HIV 
associated with reduced vulnerability to symptoms of depression during antiviral treatment for 
hepatitis C. Psychiatry Research, 253, 150 -157. do i:10.1016/j.psychres.2017.03.049;  
 
Whale, R., Fialho, R., Rolt, M., Eccles, J., Pereira, M., Keller, M., ... & Tibble, J. (2015). 
Psychomotor retardation and vulnerability to interferon alpha induced major depressive disorder: 
Prospective study of a chroni c hepatitis C cohort. Journal of psychosomatic research, 79(6), 640 -
645;  
 
Eccles, J., Lallemant, C., Mushtaq, F., Greenwood, M., Keller, M., Golding, B., ... & Whale, R. 
(2012). Pre -treatment waking cortisol response and vulnerability to interferon α induc ed 
depression. European Neuropsychopharmacology, 22(12), 892 -896. 
 
Marazziti, D., Consoli, G., Picchetti, M., Carlini, M., & Faravelli, L. (2010). Cognitive 
impairment in major depression. European journal of pharmacology, 626(1), 83 -86. 
 
McDermott, L. M., &  Ebmeier, K. P. (2009). A meta -analysis of depression severity and 
cognitive function. Journal of Affective Disorders, 119, 1 -8. doi:10.1016/j.jad.2009.04.022  
 
Senzolo, M., Schiff, S., D'Aloiso, C. M., Crivellin, C., Cholongitas, E., Burra, P., & Montagnese , 
S. (2011). Neuropsychological alterations in hepatitis C infection: the role of inflammation. 
World J Gastroenterol, 17(29), 3369 -3374  
 
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From  
inflammation to sickness and depression: when the immune system subjugates the brain. Nature 
reviews neuroscience, 9(1), 46 -56 
 
Are the methods appropriate and well  described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is re commended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of  competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation  that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, e ither now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relatin g to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I  have no competing interest  
 
I agree to the open peer review policy of the journal. I understand that my name wi ll be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available un der an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title:  Hepatitis C virus eradication improves immediate and delayed episodic memory in 
patients treated with interferon and ribavirin  
 
Version: 0 Date: 21 Aug 2017 
 
Reviewer:  Renata  Fialho  
 
Reviewer’s report:  
 
The topic is very interesting and relevant to validate the interferon model of depression and to 
provide a better care. However this manuscript needs more work, and has great potential to 
provide interesting outcomes.    
 
 
 
Abstract: this sections would benefit from some rewriting to make it look neater. It might be 
worth it clarify the times points of assessment and exclusion criteria.  
 
Introduction: this section could benefit from a more comprehensive review about hepatitis C 
treatment, the authors developed an interesting background but is lacking the inflammatory 
model of Hepatitis C which is the core of neuropsychiatric side effects.  
 
Methods: TMT test the composite B -A is missing for analysis. the Part B performance is 
indicative of ability to flexibly shift the course of an ongoing task (shifting) (Kortte et al., 2002). 
It is a pen and pencil task consisting of two parts, A and B. In part A, the  participants have to 
connect the numbers 1 to 25 in ascending order. In part B, the participants should connect the 
numbers in an ascending order but with the added task of alternating between numbers and 
letters (i.e., 1 -A-2B) (Bowie & Harvey, 2006; Corr igan, 1987). A derived score  calculated by 
(B-A) reflects the unique task requirements of part B (Corrigan & Hinkeldey, 1987; Lamberty et 
al., 1994; Lezak, 1995; Misdraju & Gass, 2010), given crucial information about processing 
speed components.   
 
Resul ts: it seems that cognitive function impairment is associated with HCV replication and 
depression symptoms presentation shows differences before and after the treatment? If so the 
paper would benefit from analysis between these components, cognition and de pression. This 
section perhaps could benefit from some more data analysis. also, it could be relevant to clarify 
the time points of assessment because of their significant impact on CNS as described previously 
in the literature, in particular with greater impact on week 4.  
 
Discussion  
 
The main outcomes are very interesting but it needs a bit more work. It is a crucial topic that 
needs clarification. It is not clear what could explain the depression symptoms not being remitted 
and what are the potential in fluences on cognitive function. Probably it would benefit this section 
a more understanding paradigm of inflammatory model of neuropsychiatric side effects of 
interferon treatment.  
The sample size is also another issue that needs to be addressed accordingl y. 
 
for reference  
 
Fialho, R., Pereira, M., Harrison, N., Rusted, J., & Whale, R. (2017). Co -infection with HIV 
associated with reduced vulnerability to symptoms of depression during antiviral treatment for 
hepatitis C. Psychiatry Research, 253, 150 -157. do i:10.1016/j.psychres.2017.03.049;  
 
Whale, R., Fialho, R., Rolt, M., Eccles, J., Pereira, M., Keller, M., ... & Tibble, J. (2015). 
Psychomotor retardation and vulnerability to interferon alpha induced major depressive disorder: 
Prospective study of a chroni c hepatitis C cohort. Journal of psychosomatic research, 79(6), 640 -
645;  
 
Eccles, J., Lallemant, C., Mushtaq, F., Greenwood, M., Keller, M., Golding, B., ... & Whale, R. 
(2012). Pre -treatment waking cortisol response and vulnerability to interferon α induc ed 
depression. European Neuropsychopharmacology, 22(12), 892 -896. 
 
Marazziti, D., Consoli, G., Picchetti, M., Carlini, M., & Faravelli, L. (2010). Cognitive 
impairment in major depression. European journal of pharmacology, 626(1), 83 -86. 
 
McDermott, L. M., &  Ebmeier, K. P. (2009). A meta -analysis of depression severity and 
cognitive function. Journal of Affective Disorders, 119, 1 -8. doi:10.1016/j.jad.2009.04.022  
 
Senzolo, M., Schiff, S., D'Aloiso, C. M., Crivellin, C., Cholongitas, E., Burra, P., & Montagnese , 
S. (2011). Neuropsychological alterations in hepatitis C infection: the role of inflammation. 
World J Gastroenterol, 17(29), 3369 -3374  
 
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From  
inflammation to sickness and depression: when the immune system subjugates the brain. Nature 
reviews neuroscience, 9(1), 46 -56 
 
Are the methods appropriate and well  described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is re commended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of  competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation  that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, e ither now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relatin g to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I  have no competing interest  
 
I agree to the open peer review policy of the journal. I understand that my name wi ll be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available un der an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title:  Hepatitis C virus eradication improves immediate and delayed episodic memory in 
patients treated with interferon and ribavirin  
 
Version: 0 Date: 21 Aug 2017 
 
Reviewer:  Renata  Fialho  
 
Reviewer’s report:  
 
The topic is very interesting and relevant to validate the interferon model of depression and to 
provide a better care. However this manuscript needs more work, and has great potential to 
provide interesting outcomes.    
 
 
 
Abstract: this sections would benefit from some rewriting to make it look neater. It might be 
worth it clarify the times points of assessment and exclusion criteria.  
 
Introduction: this section could benefit from a more comprehensive review about hepatitis C 
treatment, the authors developed an interesting background but is lacking the inflammatory 
model of Hepatitis C which is the core of neuropsychiatric side effects.  
 
Methods: TMT test the composite B -A is missing for analysis. the Part B performance is 
indicative of ability to flexibly shift the course of an ongoing task (shifting) (Kortte et al., 2002). 
It is a pen and pencil task consisting of two parts, A and B. In part A, the  participants have to 
connect the numbers 1 to 25 in ascending order. In part B, the participants should connect the 
numbers in an ascending order but with the added task of alternating between numbers and 
letters (i.e., 1 -A-2B) (Bowie & Harvey, 2006; Corr igan, 1987). A derived score  calculated by 
(B-A) reflects the unique task requirements of part B (Corrigan & Hinkeldey, 1987; Lamberty et 
al., 1994; Lezak, 1995; Misdraju & Gass, 2010), given crucial information about processing 
speed components.   
 
Resul ts: it seems that cognitive function impairment is associated with HCV replication and 
depression symptoms presentation shows differences before and after the treatment? If so the 
paper would benefit from analysis between these components, cognition and de pression. This 
section perhaps could benefit from some more data analysis. also, it could be relevant to clarify 
the time points of assessment because of their significant impact on CNS as described previously 
in the literature, in particular with greater impact on week 4.  
 
Discussion  
 
The main outcomes are very interesting but it needs a bit more work. It is a crucial topic that 
needs clarification. It is not clear what could explain the depression symptoms not being remitted 
and what are the potential in fluences on cognitive function. Probably it would benefit this section 
a more understanding paradigm of inflammatory model of neuropsychiatric side effects of 
interferon treatment.  
The sample size is also another issue that needs to be addressed accordingl y. 
 
for reference  
 
Fialho, R., Pereira, M., Harrison, N., Rusted, J., & Whale, R. (2017). Co -infection with HIV 
associated with reduced vulnerability to symptoms of depression during antiviral treatment for 
hepatitis C. Psychiatry Research, 253, 150 -157. do i:10.1016/j.psychres.2017.03.049;  
 
Whale, R., Fialho, R., Rolt, M., Eccles, J., Pereira, M., Keller, M., ... & Tibble, J. (2015). 
Psychomotor retardation and vulnerability to interferon alpha induced major depressive disorder: 
Prospective study of a chroni c hepatitis C cohort. Journal of psychosomatic research, 79(6), 640 -
645;  
 
Eccles, J., Lallemant, C., Mushtaq, F., Greenwood, M., Keller, M., Golding, B., ... & Whale, R. 
(2012). Pre -treatment waking cortisol response and vulnerability to interferon α induc ed 
depression. European Neuropsychopharmacology, 22(12), 892 -896. 
 
Marazziti, D., Consoli, G., Picchetti, M., Carlini, M., & Faravelli, L. (2010). Cognitive 
impairment in major depression. European journal of pharmacology, 626(1), 83 -86. 
 
McDermott, L. M., &  Ebmeier, K. P. (2009). A meta -analysis of depression severity and 
cognitive function. Journal of Affective Disorders, 119, 1 -8. doi:10.1016/j.jad.2009.04.022  
 
Senzolo, M., Schiff, S., D'Aloiso, C. M., Crivellin, C., Cholongitas, E., Burra, P., & Montagnese , 
S. (2011). Neuropsychological alterations in hepatitis C infection: the role of inflammation. 
World J Gastroenterol, 17(29), 3369 -3374  
 
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From  
inflammation to sickness and depression: when the immune system subjugates the brain. Nature 
reviews neuroscience, 9(1), 46 -56 
 
Are the methods appropriate and well  described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is re commended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of  competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation  that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, e ither now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relatin g to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I  have no competing interest  
 
I agree to the open peer review policy of the journal. I understand that my name wi ll be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available un der an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
assistant