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Author’s response to reviews

Title: Relationship between Negative Symptoms and Neurocognitive Functions in Adolescent

and Adult Patients with First-Episode Schizophrenia

Authors:

Manli Huang ([email protected])

Yi Huang ([email protected])

Liang Yu ([email protected])

Jianbo Hu ([email protected])

Jinkai Chen ([email protected])

Pingbo Jin ([email protected])

Weijuan Xu ([email protected])

Ning Wei ([email protected])

Shaohua Hu ([email protected])

Hongli Qi ([email protected])

Yi Xu ([email protected])

Version: 1 Date: 09 Dec 2015

Author’s response to reviews:

Dear editor,

We thank you for providing us the opportunity to revise our manuscript titled “The Relationship

between Negative Symptoms and Neurocognitive Functions in Adolescent and Adult First-

Episode Schizophrenia Patients”. We also greatly appreciate the reviewers‟ comments and

suggestions, which are very valuable for us to improve the quality of our paper. According to the

reviewers‟ suggestions, we have made significant changes to the manuscript and clarified the

corresponding aspects. We are now resubmitting our revised manuscript along with this response

letter. We have revised our paper and the major changes are shown in red. Thank you very much.

Enclosed are our point-to-point responses to the reviewer‟s critiques.

We look forward to your decision.

Sincerely,

Manli Huang, M.D.

Corresponding author:

Yi Xu

Department of Psychiatry, First Affiliated Hospital, College of Medicine, Zhejiang University,

the key laboratory of mental disorder‟s management of Zhejiang Province, No. 79, Qingchun

Road, Hangzhou 310003, China

Tel: +86-13957162975

Fax: +86-571-56723001

Email: [email protected]

#Manli Huang and Yi Huang contributed equally to this work.

Reviewer #1: BMC Psychiatry Manuscript Review: 10.12.15

Question 1:

The research question posed by the authors is not easily identifiable and understood.

Specifically, the arguments leading up to the study objectives do not clearly flow; it is unclear

why these 3 objectives were selected, based upon what is presented above in the introduction.

Response:

Thank you for your advice. We are so sorry to bring you so much trouble because of our

inappropriate expression. We have modified paragraph 3, 4, 6, 7 of Background section to make

it clear.

Question 2:

In paragraph 5 under Background, the ideas and how they link together are difficulty to follow.

Also, the authors state, “So we assume that the severity of negative symptoms in adolescent

schizophrenia patients is more closely related to their neurocognitive deficits” – However, this

assumption was not supported by the text above. The authors need to clarify their points and

make it clear to the reader why they are making this assumption that will then lead to the

hypotheses and study objectives.

Response:

The advice is valuable. We have increased related content in paragraph 6 of Background section:

Since both symptoms and neurocognitive deficits may be caused by neurodevelopmental

problems in adolescent first-episode schizophrenia patients whose prefrontal cortices are under

developing, we assume that their negative symptoms are more closely related to neurocognitive

deficits than adult first-episode schizophrenia patients with developed prefrontal cortices.

Question 3:

Also, because the association between neurocognition and negative symptoms has been widely

studied before in chronic schizophrenia – highlighting that literature would allow for the

argument for this study in FEP (adolescent vs adult).

Response:

Thank you for your advice. We have highlighted related content in paragraph 5 of Background

section.

Question 4:

The authors should consider avoiding the use of colloquial language – particularly that which is

not fully accurate. For instance, saying the “causes of schizophrenia have been hotly debated”

although true perhaps in part, this suggests more consensus to a single theory than there is in the

field. Consider replacing these type of statements with more accurate wording such as “widely

investigated.”

Response:

Thank you for your advice. We are so sorry to bring you so much trouble because of colloquial

language. We have undertaken additional editing.

Question 5:

It is unclear why the authors mention that schizophrenia is often characterized by “aggressive

behaviour” – as this seems stigmatizing and is not grossly accurate. If they are going to make this

sort of potentially stigmatizing statement / use this descriptor – it should be cited and justified

within the context of the introduction.

Response:

The advice is valuable. We are so sorry to bring you so much trouble because of our

inappropriate expression. We have used the word “hyperactivity” instead.

Question 6:

There are several grammatical languages errors, such as line 48 under Background where it says

“Literature researches suggested.....” Please re-read carefully and correct such mistakes.

Response:

We are so sorry that some grammatical and spelling errors occur in the manuscript. We have

undertaken additional editing.

Question 7:

In paragraph 3 under Background, negative symptoms are described. However, the descriptions

are somewhat unclear to the reader. For instance, it is unclear what “feeling difficult in speech”

means? Also – the authors may consider either using descriptors only – such as “failure in

experience (experiencing?) pleasure – or the technical terms, which in this case would be

„anhedonia‟ Instead – what is seen is a mixture of description and terms, such that it is confusing

to the reader.

Response:

Thank you for your advice. We are so sorry to bring you so much trouble because of colloquial

language. We have undertaken additional editing.

Generally，negative symptoms refer to poor emotional reactions or thought

processes，including emotion impoverishment，speech barrier，mood depression and activity

decrease.

Question 8:

In paragraph 4 under Background, It would be helpful to the reader to connect the constructs of

interest (such as executive function) to the tests being described. As it is – it seems they are just

listed and unlinked to one another. The last sentence in this paragraph does not make sense –

please clarify its meaning so that it can be linked to future points.

Response:

The advice is valuable. We have added related content in new paragraph 5 of Background

section:

Patients with higher negative scores of PANSS had more PE and fewer CC in WCST (standing

for executive function), and poorer University of Pennsylvania Smell Identification Test

performance (standing for function of an individual's olfactory system). They also experienced

more difficulties in Trail Making Test (standing for visual attention and executive function),

Verbal Fluency Test (standing for semantic memory) and Faux Pas test (standing for sociability).

Question 9:

Please specify how reliability in your PANSS assessment was established and what it was.

Without reliable testing, your results may be invalid.

Response:

Thank you for your advice. All psychiatrists have been measured inter-rater agreement of

PANSS, and the Kappa Coefficient is 0.80.

Question 10:

The control group seemed appropriate, however, the ratio of Male to Female participants seemed

different between groups. This seems like something worth mentioning – at very least in the

discussion.

Response:

The advice is very important and valuable. Our research includes all eligible patients and healthy

controls, but the ratio of Male to Female participants is different between groups. We have added

related content in “limitations” of Discussion section.

Question 11:

Also – the fact that the majority of participants in the FEP group were female makes this study

somewhat unique (many studies in this population are mostly male). This should be addressed

and implications discussed.

Response:

The advice is very important and valuable. Our research includes all eligible patients and healthy

controls, but the ratio of Male to Female participants is different between groups. We have added

related content in “limitations” of Discussion section.

Question 12:

It is unclear what version of the SCID was used. There is no reference for DSM or SCID – please

include.

Response:

The advice is very important and valuable. We have added related content in “Study subjects” of

Methods section:

The Structured Clinical Interview for DSM-IV-TR (SCID), routine laboratory tests, and

physical and neurological examinations were all administered to each participant.

Question 13:

More detail needed for Methods. It seems somewhat unclear how the nuts & bolts of the study

were accomplished.

Response:

The advice is very valuable. We have modified the Method section to make it clear.

Question 14:

Under “Study subjects” – it says all participants had „no MRI evidence of structural brain

abnormalities‟ but there is no further description as to how this was determined – who did it?

What were the procedures? Etc...

Response:

The advice is very important and valuable. We have added related content in paragraph 3 of

Method section:

All volunteers accepted Magnetic resonance imaging performed by experienced professional

staff in the First Affiliated Hospital of Medical School of Zhejiang University using the Philips

Magnetic Resonance Imaging Systems Achieva 3.0 T TX (Philips Healthcare, Netherlands). The

system was tested for data stability prior to use, and MRI was finished within one week after

neuropsychological tests.

Question 15:

Were all the tests performed in English? If not, please specify how modifications were made to

account for translation.

Response:

The advice is very important and valuable. All the tests performed in Chinese, both PANSS and

neuropsychological assessments have been widely used in China. We had standard Chinese

versions of them. Related content has been modified in our manuscript.

Question 16:

It states in the Methods section that the Neuropsychological tests were performed by “fully

trained psychiatrists.” As it is not always standard practice for these tests to be completed by

physicians, it would be helpful to very briefly describe the training procedures.

Response:

Thank you for your advice. Fully trained psychiatrists mean physicians taking consistent

training courses in Department of Psychiatry, First Affiliated Hospital, College of

Medicine, Zhejiang University.

The tests were completed for all subjects by fully trained psychiatrists with consistent training

courses in Department of Psychiatry, First Affiliated Hospital, College of Medicine, Zhejiang

University. All psychiatrists have been measured inter-rater agreement of PANSS, WCST, CPT,

TMT and SCWT, and the Kappa Coefficient was 0.80, 0.82, 0.78, 0.83 and 0.84, respectively.

Question 17:

Please specify the version of CPT you used, including that it was computerized.

Response:

The advice is very important and valuable. All the tests performed in Chinese, both PANSS and

neuropsychological assessments have been widely used in China. We had standard Chinese

versions of them. Related content has been modified in our manuscript.

Question 18:

Please cite Table 1 in your Statistical Analyses section so that the reader can better follow your

description.

Response:

Thank you for your advice. We have cited Table 1 in our Statistical Analyses section.

Question 19:

It seems like one of the strengths of the methods is that the authors have determined who had

their first-episode as an adult versus who had their first episode as an adolescent. I think this is

meant to be at the core of the study- however that is unclear until the reader is more than half

way done reading the ms. Please consider revising / restructuring the introduction and methods

to make this clear.

Response:

Thank you for your advice. We have added related content in Background section, especially in

objectives:

The present study had three objectives (The first two items are replication of previews studies in

some degree, while the 3rd objective is novel in our study):

1. To evaluate neurocognitive deficits and clinical symptoms of first-episode schizophrenia

patients.

2. To study the relationship between negative symptoms and neurocognitive functions in

first-episode schizophrenia patients with a 5-factor model.

3. To compare the correlations of negative symptoms and neurocognitive functions between

adolescent and adult first-episode schizophrenia patients.

Question 20:

It is unclear why the authors chose to do a new factor analysis on the PANSS items, rather than

using a standard 5-factor form, which would have already been available (superiority of fit over

3 factor mentioned but not others). What was the theoretical reasoning behind this? Please

specify this choice. Also, please describe why this is an advantage / important.

Response:

Thank you for your advice. We deleted the factor analysis of the PANSS in this study, and used

an admitted five factor model of Chinese version PANSS instead.

Question 21:

Did the authors look at the duration of illness as a potential confounding factor? It is unclear.

This could be addressed by inclusion into the partial correlation?

Response:

Thank you for your advice. The duration of illness is not a potential confounding factor in our

study. There are 2 reasons as follow:

1. There was no significant difference in duration of illness between adolescent and adult

first-episode schizophrenia patients. Details are displayed in Table 2.

2. There were only 2 significant correlations between duration of illness and

neuropsychological assessments. Details are displayed in Table 3.

Question 22:

From the description under “Statistical Analyses” it looks like the correlation between negative

factor and neuropsych accounted for education but the general conditions and neuropsych did

not? Is this what was intended? If not, please clarify.

Response:

We do not know if we understand your question or not. We mean education level is one

of general conditions. We found significant correlations between the education level and

neuropsychological assessments on 9 items, while there were less correlations between

other general conditions and neuropsychological assessments.

Question 23:

From your description under “Statistical Analyses” – please provide more detailed information

regarding how you calculated the “difference in correlations coefficients between adolescent and

adult first-episode schizophrenia patients. “ Also, please provide reference for transformation (in

order to enable future replication).

Response:


inappropriate expression. We used the Fisher‟s Z test to compare the correlations, but our

expression in manuscript is not clear to readers. We have increased related content in “statistical

analyses” of Methods section and table 4 to make it clear:

The difference in correlation coefficients between adolescent and adult first-episode

schizophrenia patients was computed by a Fisher‟s Z test.

Question 24:

Please take care to cite the Tables as you are describing the data. Your results are complicated

and this would make it much easier to understand and follow.

Response:


inappropriate expression. We have cited the Tables in manuscript to make our results much

easier to understand and follow.

Question 25:

Under section 3.4 in the Results, the authors say, “So far, we have proven (as an aside, this is a

questionable use of wording) that there were significant correlations between the negative factor

and most neuropsychological assessments in first-episode schizophrenia patients, but no strong

correlation was found.” This seems to be completely contradicting itself. Please clarify.

Response:

The advice is very important and valuable. The word "proven" in the manuscript has been

replaced by “supported”, “suggested” or “showed”, etc.

We are so sorry to bring you so much trouble because of our inappropriate expression. We mean

that the negative factor was moderately correlated to SCWT 1 (r = 0.410, P < 0.001) and SCWT

3 (r = 0.409, P < 0.001), and in other neuropsychological assessments, only weak correlations

could be found. But there were correlations between the negative factor and most

neuropsychological assessments in first-episode schizophrenia patients. We have deleted the

confusing sentence.

Question 26:

In the first paragraph of the discussion, the authors conclude “That is to say, schizophrenia

should be viewed as a „neurocognitive disorder‟.” This is a big statement from the limited sample

/ evidence that this report in and of itself provides. If such a statement is to be made, it should

likely be „toned down‟ and placed after the review of other studies (with which this one provides

data consistent).

Response:

Thank you for your advice. We have deleted the claim that is too strong for the data

provided.

Question 27:

It seems that the major implication of this paper is that the severity of negative symptoms in

those with FEP diagnosed in adolescents may be more strongly linked to poor neurocognition

than in those diagnosed as adults. Further discussion of this finding would substantially improve

the ms. Why is this important? What does this means for the field? Are there implications for

treatment?

Response:

Thank you for your advice. We have highlighted the importance of our research

outcomes in paragraph 6 of Discussion section.

Question 28:

While, the present manuscript is written fairly well, a number of grammatical, spelling, and

spacing errors need to be addressed.

Response:



Question 29:

Also – the organization could use further thought to help the reader follow the flow of the

findings and how the pieces fit together.

Response:

Thank you for your advice. We have reorganized the manuscript to help the reader follow

the flow of the findings and how the pieces fit together.

Reviewer #2: BMC Psychiatry Manuscript Review: 10.19.15

Question 1:

Background (pg. 2): The rationale for the author's statement that adolescence is the main reason

for the link between negative symptoms and cognitive functioning is never provided. This claim

needs to be removed or the author's need to provide evidence for this statement. In general, the

author's should provide more discussion about why adolescence is an important time for both

negative symptoms and cognitive functioning. We know that early onset is linked to worse long-

term functioning: what is the importance of adolescence in this relationship?

Response:

The advice is very important and valuable. We have accepted the reviewer‟s advice and

removed the claim. On the other hand, we have provided more information on the importance of

adolescence in paragraph 4 of Background section.

Question 2:

Background: Related to the first concern, the authors also do not provide rationale as to why

negative symptoms would be more closely tied to neurocognitive deficits in adolescence

compared to chronic patients. Regarding novelty, this is the key question in this study. Thus, it is

critical to give the reader an opportunity to evaluate why one might expect to see a stronger link

in adolescents.

Response:

The advice is valuable. We have increased related content in paragraph 6 of Background

section:

Since both symptoms and neurocognitive deficits may be caused by neurodevelopmental

problems in adolescent first-episode schizophrenia patients whose prefrontal cortices are under

developing, we assume that their negative symptoms are more closely related to neurocognitive

deficits than adult first-episode schizophrenia patients with developed prefrontal cortices.

Question 3:

Background: It would be helpful to highlight what is novel in this study (e.g., adolescents

compared to chronic on negstive symptoms-neurocognition link) compared to what is strictly

replication (e.g., negative symptoms and neurocognitive deficits linked, neurocognitive deficits

worse in these groups compared to controls).

Response:

Thank you for your advice. We have increased related content at the end of Background

section:

The present study had three objectives (The first two items are replication of previews studies in

some degree, while the 3rd objective is novel in our study).

Question 4:

Hypothesis/Method: It is unclear why the authors conducted a factor analysis of the PANSS in

this study. As they point out, the five factor model is widely accepted. The factor analysis does

not necessarily add to or compliment the primary findings in this study. The paper would benefit

from citing the literature pointing to the five factor model and using that model. The authors

could then remove these analyses and focus more on their primary questions. As it stands, there

is not rationale for this hypothesis and the hypothesis is surprising to readers.

Response:



Question 5:

Analyses: A major criticism of the analysis approach is that the authors appear to be setting up a

comparison of the neurocognition-negative symptoms relationship in first-episode versus chronic

patients. However, the analysis plan is not appropriate for these comparisons. To compare

groups, the authors should actually compare the correlations (example: Fischer's r to z

transformations) rather than simply reporting what was significant in one group and non-

significant in another. With the current analyses, the authors should not make claims that these

correlations are more strongly linked in one group versus another.

Response:


inappropriate expression. We used the Fisher‟s Z test to compare the correlations, but our

expression in manuscript is not clear to readers. We have increased related content in “statistical

analyses” of Methods section and new table 4 to make it clear:

The difference in correlation coefficients between adolescent and adult first-episode

schizophrenia patients was computed by a Fisher‟s Z test.

Question 6:

Discussion: It would be helpful if the authors listed their most important findings first (following

a summary paragraph and then went in order of significance (of findings) in subsequent

paragraphs. Further, the Discussion reads more like a restatement of results rather than a

discussion of why the authors believe their findings occurred.

Response:

The advice is very important and valuable. We have added related content at first

paragraph of Discussion section:

The current study found that there were significant correlations between the negative factor and

most neuropsychological assessments in first-episode schizophrenia patients, especially on

SCWT 1 and SCWT 3. In adolescent schizophrenia patients, the negative factor was strongly

correlated to more time spent in part 1 and part 2 of TMT, and it was moderately or weakly

correlated to more PE and fewer CC of WCST, fewer CPT 1 and CPT 2 correct trials. However,

no correlation could be found in adult patients in the above items.

Question 7:

The writing is mostly correct (in terms of structure), but there are several passages where errors

occur (e.g., "feeling difficult in speech"). It would be helpful for readers if additional editing

were undertaken.

Response:

We are so sorry that some grammatical and spelling errors occur in the manuscript. We

have undertaken additional editing.

Question 8:

Abstract: Don't use abbreviations without referencing the full measure first.

Response:

The advice is valuable. Abbreviations in abstract have been replaced.

Question 9:

Abstract and Pg. 1: What is 'abnormal social behavior?' Provide examples as to what you are

referring to.

Response:

The advice is very important and valuable. We have added related content.

Question 10:

Method: How is 'planning to be pregnant' defined? If someone was ever planning to be pregnant

were they excluded or within X amount of months? Provide more information here.

Response:

The advice is valuable. “Planning to be pregnant” means “planning to be pregnant within 6

months”.

Question 11:

Method: Give examples of PANSS symptoms on the other three factors in addition to positive

and negative symptoms.

Response:

Thank you for your advice. But we are so sorry that we can‟t totally understand the

question.

The 5-factor model of Chinese version PANSS includes negative, positive, excitement-

hostile, anxiety depression and cognitive defect?

Question 12:

Analyses: I agree with the authors controlling for education but a brief line explaining

why this was necessary is warranted.

Response:

The advice is valuable. We have added related content in paragraph 6 of Results section:

1. We found that there were significant correlations between the education level and

neuropsychological assessments on 9 items, especially on TMT 1 (r = -0.462, P < 0.001),

TMT 2 (r = -0.473, P < 0.001), SCWT 1 (r = -0.406, P < 0.001) and SCWT 2 (r = -0.432,

P < 0.001).

2. It has been reported in the previews study that education had the correlations with

cognitive impairments in Deficit schizophrenia.

Question 13:

Analyses: The phrase "compared by hypothesis testing" is unclear. What specific tests were run?

Response:

Thank you for your advice. We are so sorry to bring you so much trouble because of our

inappropriate expression. We used the Fisher‟s Z test to compare the correlations.

Question 14:

Results: Provide the chi-square value for gender in text.

Response:

The advice is valuable. We have provided the chi-square value for gender in table 1.

Question 15:

The use of the word "proven" in the manuscript is problematic. Theories can be supported but

not proven.

Response:



Question 16:

Tables 4 and 5: It would be helpful for readers if specific correlations were given as opposed to

simply stating "ns" for non-significant findings.

Response:

Thank you for your advice. We have put specific correlations in new Table 3, 4 and 5

instead of simply stating "ns" for non-significant findings.

Reviewer #3:

Question 1:

The manuscript would be significantly improved with extensive editing for language. There are

many instances in the paper where language is used in a confusing manner that obscures the

message of the paper.

Response:



Question 2:

The authors conduct a huge number of analyses, without attention to inflation of Type I error

rate. With this number of analyses, a correction of some kind should be applied.

Response:

Thank you for your advice. We have decreased a huge number of analyses to avoid Type

I error.

Question 3:

The proposed aims and described conclusions of the paper don't seem to match the methods and

results. In the introduction, authors describe that previous work examining relationships between

symptoms and neurocognition did not put forward a model of why these constructs were related.

This paper doesn't appear to do that either.

Response:

The advice is very important and valuable. We are so sorry to bring you so much trouble because

of our inappropriate expression. The most important objective in our study is to compare the

correlations of negative symptoms and neurocognitive functions between adolescent and adult

first-episode schizophrenia patients. We have modified the Background section to make it clear.

Question 4:

The factor analysis on the PANSS is not adequately described. Shifting from the initial 9-factor

to 5-factor model is supported by previous research, but if the authors were only interested in a

confirmatory replication of previous work on the PANSS, it's unclear why an exploratory

analysis would have been conducted in the first place.

Response:



Question 5:

The introduction has a number of language errors that obscure the message (e.g. schizophrenia

"causes disability-adjusted life years...").

Response:

We are so sorry that some grammatical and spelling errors occur in the manuscript. We

have undertaken additional editing. While the disability-adjusted life year (DALY) is a

measure of overall disease burden, expressed as the number of years lost due to ill-health,

disability or early death.

Question 6:

The premise that neurocognitive impairments emerge "earlier" in first-episode rather than

chronic patients is circular. It's also unclear what's meant by that. Don't all psychological

characteristics emerge earlier in younger participants?

Response:

The advice is very important and valuable. We are so sorry to bring you so much trouble because

of our inappropriate expression. We have deleted the unclear sentence.

Question 7:

The term "adult" doesn't seem appropriate to me - all participants in the study are adults. Some

are first-episode, whereas others are more chronic.

Response:

We are so sorry to bring you so much trouble because of our inappropriate expression. Not all

participants in the study are adults, but all of them are first-episode schizophrenia patients. Some

are adolescents, whereas others are adults.

Question 8:

The background justification is unclear. Is the present study replicating the factor structure of the

PANSS? Is it trying to put forward a model of relationships (i.e. temporal) between

neurocognition and negative symptoms? The justification doesn't appear to match proposed

analyses.

Response:

We are so sorry to bring you so much trouble because of our inappropriate expression.

We have modified the Background section to make it clear. There are three objectives,

while the first two items are replication of previews studies in some degree, while the 3rd

objective is novel in our study.

Question 9:

Just a comment - it is interesting that the paper has a collection of participants that are drug

naive. This could be a possible specific contribution of the paper.

Response:

All participants in the study are first-episode schizophrenia patients,

Question 10:

Is there a reason the time of testing is relevant here.

Response:

The advice is very important and valuable. We have increased relevant explanation in

paragraph 5 of Method section:

For reducing errors, all items were assessed in the morning, and neuropsychological tests were

administered first.

Question 11:

Measure selection should be outlined in greater detail. How did the researchers choose these

specific cognitive tasks, and why are all included?

Response:

The advice is very important and valuable. We have increased relevant explanation in paragraph

6 of Method section. And details have been outlined in subsection.

Question 12:

The description of SCWT 2 is unclear. I believe I understand what authors intend to say, but this

should be reviewed for clarity.

Response:

We are so sorry to bring you so much trouble because of our inappropriate expression. We have

modified relevant content to make it clear:

The Stroop Color-Word Test, also called Stroop Test, is considered to measure selective

attention, cognitive flexibility and processing speed, and it is used as a tool in the evaluation of

executive functions. In step 1 of SCWT (SCWT 1), the subjects were asked to read out three

black words as fast as possible, which stand for a certain color respectively. Then, in step 2

(SCWT 2), they were instructed to tell the color of three color parcels as fast as possible. Finally,

in step 3 (SCWT 3), they were required to tell the color of three color-words as fast as possible,

while each color was different from the word‟s meaning. The performance for each condition

was calculated by the processing time per item in seconds. The reaction time (RT of SCWT)

difference in part 3 relative to part 2 was called the “interference” effect.

Question 13:

Why are analyses two tailed? It appears in hypotheses that participants have an expected

direction of effect.

Response:

Thank you for your advice. Although we have an expected direction of effect, we still believe

that results of two-tailed statistical tests are more convincing.

Question 14:

The justification and model driving the decisions in the factor analysis should be detailed in

greater depth. Why was an exploratory analysis conducted if a confirmatory model was to

follow? Is this aiming to replicate the Bell 5-factor model?

Response:



Question 15:

Use of the word "proven" should not be used in correlational analyses.

Response:



Question 16:

The conclusion that "schizophrenia should be viewed as a neurocognitive disorder" is too strong

for the data provided.

Response:

Thank you for your advice. We have deleted the claim that is too strong for the data

provided.

Question 17:

The end of the second paragraph that compares the current study results to previous work is very

unclear. What is meant by "opposite results"? With which variables?

Response:

We are so sorry to bring you so much trouble because of our inappropriate expression. We have

modified relevant content to make it clear:

But some previous studies showed that adolescent schizophrenia patients performed

worse than adult patients in tasks of working memory, language and motor function.

Question 18:

Conclusions from the current study about ordering of emergence of symptoms and causal models

cannot be drawn. The study is only correlational and does not predict changes over time.

Response:

The advice is very important and valuable. We have modified relevant content:

Most importantly, our findings suggested that there were closer correlations between the

negative factor and some neuropsychological assessments outcomes in adolescent first-episode

schizophrenia patients, including more time spent in TMT 1, TMT 2 and SCWT 2, fewer times

of CPT 1, CPT 2 and CPT 3, as well as more PE of WCST, compared with adult patients.

Therefore, the severity of negative symptoms in adolescent schizophrenia patients is more

related to their neurocognitive deficits of visual, selective and sustained attention, visual search

and processing speed, mental and cognitive flexibility, as well as executive function. Some of the

latest research regarded schizophrenia as a collection of „neurodevelopmental disorders‟, because

it nearly always emerges in late adolescence or early adulthood, when the prefrontal cortex is

still developing. Our results partly support the conclusion. Because adolescence is a key period

of neurological and psychological development, earlier schizophrenia symptoms and

neurocognitive deficits may both come from earlier neurodevelopmental problems in adolescent

first-episode schizophrenia patients. In this way, adolescent schizophrenia patients‟ negative

symptoms are more closely related to their neurocognitive deficits, compared with adult first-

episode schizophrenia patients. Based on this correlation, obvious negative symptoms may

suggest serious neurocognitive deficits for adolescent schizophrenia patients.

EDITOR'S REQUEST:

Question 1:

Please clarify if consent for study participants under 16 years.

Response:

We have increased relevant explanation in paragraph 4 of Method section.

All subjects and their legal guardians (if participants were under 16 years) were provided with

written informed consent before entering the study.

Question 2:

Please include conclusions section.

Response:

We have increased conclusions section.

Question 3:

Please reformat Authors' Contributions to include initials of all authors.

Response:

Thank you for your advice. We have modified the Authors' contributions section.

YX planed and drafted the study, MLH designed the study, collected the data and advised on

modeling strategies, YH analyzed the data and wrote the paper, JBH evaluated the scales, LY,

JKC, PBJ, WJX, NW, SHH and HLQ collected the data. MLH and YH contributed equally to

this work.

Thank you for your hard work again and we hope you will be satisfied with our replies. We are

ready to deal with the questions if you have any. Many thanks!

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