Identifying Neurobiological Markers in Obsessive–Compulsive Disorder: A Study Protocol for a Cross-Sectional Study in Subgroups of Differing Phenotype

Round 1

Reviewer 1 Report

The author Pasquale Paribello et al “Identifying neurobiological markers in obsessive-compulsive disorder: a study protocol for a cross-sectional study in subgroups of differing phenotype” is a well-written and informative article that addresses the epidemiology and disease burden of obsessive-compulsive disorder despite a growing body of evidence suggesting the possibility of finding specific biomarkers that might support clinicians in distinguishing individuals living with OCD from healthy controls.

 Major Comments:

 

1)      It would help if the study clearly define the expected different between classic OCD forms and OCDPANS, OCDEO and OCDLO and OCDPI and other OCD subgroups in terms of clinical, neurocognitive, neurophysiological and biological markers. 

2)      It would be useful to describe the criteria used to define the OCD subgroups, and would be useful to describe the criteria used to distinguish between these subgroups, such as the age of onset, duration and severity of symptoms.

3)      The study does not describe the methods used to analyze the biological markers

4)      The study mentions the analysis of blood samples to identify biomarkers, but it does not specify which markers will be analyzed or the methods used for analysis. It would be useful if sample size may not be sufficient to detect significant differences between subgroups, particularly for OCDPANS, which is relatively rare conditions.

5)      The author should mention about potential implications of the study findings beyond OCD, which could have implications for understanding related psychiatric disorders or neuropsychiatric conditions.

There is nothing much to work on the English language.

Author Response

1)      It would help if the study clearly define the expected different between classic OCD forms and OCDPANS, OCDEO and OCDLO and OCDPI and other OCD subgroups in terms of clinical, neurocognitive, neurophysiological and biological markers.
R) Thank you for your comment. The draft has been edited as follows:
“Considering the exploratory nature of the present study, it is difficult to hypothesize the di-rection of the observed difference in terms of either neuropsychological tests, plasma biomarkers, EEG/polysomnographic markers or indeed the required sample size to detect a difference between study groups. Notwithstanding these limitations, we anticipate:

• 
  Higher symptoms severity for OCDEO vs OCDLO;
  •           Worse cognitive performances for OCDPANS vs OCDEO and OCDLO;
  •           Greater impact on sleep architecture for OCDPANS as compared with the remaining sub-types.”

 

2)      It would be useful to describe the criteria used to define the OCD subgroups, and would be useful to describe the criteria used to distinguish between these subgroups, such as the age of onset, duration and severity of symptoms.

R) Thank you for your comment. The draft has been edited as follows:
“Considering the exploratory nature of the present study, it would be difficult to hypothesize the di-rection of the observed difference in terms of either neuropsychological tests, plasma biomarkers, EEG/polysomnographic markers or indeed the required sample size to detect a difference between study groups. Notwithstanding the aforementioned limitations, we anticipate:
OCDEO: defined on the base of symptoms onset ≤17 years of age [15];
•           OCDLO: defined on the base of symptoms onset after age 17 [15] with a total BABS score < 13 [23];

• OCDPANS: defined according to the National Institute of Health 2010 pediatric acute-onset neuropsychiatric syndrome (PANS) criteria [24];
• OCDPI: defined according to a total BABS score ≥ 13 points [23] with age of onset > 17 years of age.”

 

3)      The study does not describe the methods used to analyze the biological markers

R) The method section has been now expanded as requested.

4)      The study mentions the analysis of blood samples to identify biomarkers, but it does not specify which markers will be analyzed or the methods used for analysis. It would be useful if sample size may not be sufficient to detect significant differences between subgroups, particularly for OCDPANS, which is relatively rare conditions

R) Thank you for your comment. The draft has been edited as follows:
“At the moment of recruitment, we will collect blood samples that will be used for peripheral bi-omarker analyses (i.e., BDNF, S100β, pro-inflammatory markers (IL-1β, TNF-α) and C‐reactive protein (CRP))”

And:
“Considering the exploratory nature of the present study, it is difficult to hypothesize the di-rection of the observed difference in terms of either neuropsychological tests, plasma biomarkers or EEG/polysomnographic markers or indeed the required sample size to observe a difference between study groups. Notwithstanding these limitations, we anticipate:
•           Higher symptoms severity for OCDEO vs OCDLO;
•           Worse cognitive performances for OCDPANS vs OCDEO and OCDLO;
•           Greater impact on sleep architecture for OCDPANS as compared with the remaining sub-types.”

5)      The author should mention about potential implications of the study findings beyond OCD, which could have implications for understanding related psychiatric disorders or neuropsychiatric conditions.

R) Thank you for your comment. The draft has been edited as follows:
“Moreover, depending on the results of the present project, we might gain additional insight into closely related conditions such as body dysmorphic disorders or eating disorders. Arguably, a sizeable portion of early onset eating disorders may instead be more correctly classified as a pediatric acute-onset neuropsychiatric syndrome. Gaining additional insight into potential biological, neuropsychological EEG/polysomnographic differences between different OCD subgroups may further in-form diagnostic algorithms for related disorders.”

Reviewer 2 Report

The proposed study is well written, cohesive and aims to address some of the gaps in research concerning OCD both in adults and adolescents. The study once performed will definitely benefit patients and help design better therapies for treatment. The projected outcomes of this 2 year study will help us have a better picture of the different elements that define a particular OCD subtype including the bio-markers and their associated treatment response. Adequate funding for the study is requited. The study is complete in itself . However , I just had the following suggestions  that the authors can include in order to enhance the quality of their. Here are my suggestions, 

1. For the Sleep study the authors should include a "Sleep latency" tab for their patients as this a widespread problem in different OCD patients.

2. Some personal history of the study participants should be included - Like family history, any record of trauma, parents occupations, etc . This can help with delineating the various triggers for OCD and whether these are associated with any particular subtype.

3. Additional, biomarkers for associated syndromes should also be tested. Like with patients with tourette syndrome -L-pipecolic acid levels should be added. The pharmacological interplay of these factors needs to be studied.

Author Response

1)For the Sleep study the authors should include a "Sleep latency" tab for their patients as this a widespread problem in different OCD patients.

R) Thank you for your comment. The draft has been edited as follows:
“Pittsburg Sleep Quality Index assessing 1) subjective sleep quality, 2) sleep latency, 3) sleep duration, 4) usual sleep efficiency, 5) sleep disorders, 6) use of hypnoinducent, 7) diurnal dysfunction.”

 

2)Some personal history of the study participants should be included - Like family history, any record of trauma, parents occupations, etc . This can help with delineating the various triggers for OCD and whether these are associated with any particular subtype.

R) Thank you for your comment. The draft has been edited as follows:
“All study population: sociodemographic, personal and family history comprising: 1) patient’s ethnicity, 2) psychiatric comorbidities, 3) medical comorbidities, 4) father's age at birth, 5) mother's age at birth, 6) socio-economic status (self-assessed on three levels), 7) education level, 8) father ethnicity, 9) mother ethnicity, 10) family history of mental disorders, 11) family history of suicide behaviors”

3)Additional, biomarkers for associated syndromes should also be tested. Like with patients with tourette syndrome -L-pipecolic acid levels should be added. The pharmacological interplay of these factors needs to be studied.

R) Thank you for your comment. Unfortunately, at this stage the funding available for this project would not allow us to add more biomarkers to the described test panel.

Round 2

Reviewer 1 Report

Dear Authors,

Thank you for incorporating all the comments as mentioned.