{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:13:03Z","timestamp":1772169183047,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.20557.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000}}],"reference-count":44,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["226787"],"award-info":[{"award-number":["226787"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>Many people with bipolar disorder have disrupted circadian rhythms. This means that the timing of sleep and wake activities becomes out-of-sync with the standard 24-hour cycle. Circadian rhythms are strongly influenced by light levels and previous research suggests that people with bipolar disorder might have a heightened sensitivity to light, causing more circadian rhythm disruption, increasing the potential for triggering a mood switch into mania or depression. Lithium has been in clinical use for over 70 years and is acknowledged to be the most effective long-term treatment for bipolar disorder. Lithium has many reported actions in the body but the precise mechanism of action in bipolar disorder remains an active area of research. Central to this project is recent evidence that lithium may work by stabilising circadian rhythms of mood, cognition and rest\/activity. Our primary hypothesis is that people with bipolar disorder have some pathophysiological change at the level of the retina which makes them hypersensitive to the visual and non-visual effects of light, and therefore more susceptible to circadian rhythm dysfunction. We additionally hypothesise that the mood-stabilising medication lithium is effective in bipolar disorder because it reduces this hypersensitivity, making individuals less vulnerable to light-induced circadian disruption. We will recruit 180 participants into the HELIOS-BD study. Over an 18-month period, we will assess visual and non-visual responses to light, as well as retinal microstructure, in people with bipolar disorder compared to healthy controls. Further, we will assess whether individuals with bipolar disorder who are being treated with lithium have less pronounced light responses and attenuated retinal changes compared to individuals with bipolar disorder not being treated with lithium. This study represents a comprehensive investigation of visual and non-visual light responses in a large bipolar disorder population, with great translational potential for patient stratification and treatment innovation.<\/ns3:p>","DOI":"10.12688\/wellcomeopenres.20557.2","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T07:45:09Z","timestamp":1729237509000},"page":"64","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating light sensitivity in bipolar disorder 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.22755.r76484, Yuichi Esaki, Fujita Health University School of Medicine, Toyoake, 20 Mar 2024, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-64\/v1#referee-response-76484","order":0,"name":"referee-response-76484","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Amber Roguski<\/b>; \n<i>Posted: 18 Apr 2024<\/i>; We thank the reviewer for their careful consideration of the HELIOS-BD study and their thoughtful questions and suggestions. Our responses are as follows, and we will make amendments to the manuscript in due course to provide further clarification on the below points.  \n<b>Reviewer Comment:<\/b> 1. Figure 2. Do the participants take part in all parts, including Part A, B, and C? Or do they take part in only one part? -  A) Participants are expected to complete all parts of the study (Baseline, Part A-C) and are recruited onto the study under that expectation.  \n<b>Reviewer Comment:<\/b> 2. Page 9. 3.4.4.3 Part B: Retinal assessments \u201cExperimental assessments will be conducted at the Colour and EEG laboratories (Dugald Stewart Building, University of Edinburgh)&nbsp;\n<u>between the months of September\u2013April<\/u>&nbsp;inclusive to avoid the effects of too much light at night during the summer months.\u201d Page 11. 3.5 Data collection\/participation windows \u201cBaseline,&nbsp;\n<u>Part B and Part C study visits and data collection will take place throughout the year.\u201d<\/u> Which is correct? Will Part B study data collection take place between the months of September\u2013April or throughout the year?  A) Thank you for highlighting this inconsistency \u2013 Baseline, Part B and Part C appointments will take place throughout the year. Only Part A appointments are stopped during the months of May \u2013 August (inclusive). We will amend the manuscript accordingly.  \n<b>Reviewer Comment:<\/b> 3. Page 11. 3.6 Study population This is a longitudinal study. What happens if a participant taking lithium stops taking it during follow-up? Drop out? Or will the data be included in the analysis? Also, what happens if a participant not taking lithium starts taking it during follow-up?  A) Inclusion criteria for the two bipolar groups state that participants must have been taking lithium consistently for the past 6 months (bipolar on lithium group) or have not taken lithium for the past 6 months (bipolar not on lithium group). A change in lithium medication, either stopping or starting, would therefore serve as an exclusion criterion and make the participant in question ineligible for continued participation. If a participant therefore has a lithium-related medication change, they are withdrawn from the study. Their data up to the change would be kept and included in analyses.  \n<b>Reviewer Comment:<\/b> 4. Page 12. BD Lithium participant group Who and how determine clinically euthymic of the participants? For example, the International Society for Bipolar Disorders Task Force recommends a MADRS or YMRS score of &lt;8 points to indicate symptomatic remission of bipolar depression or mania, respectively (Tohen et al., 2009). Do the authors assess mood symptoms at the baseline assessment?  A) Euthymic mood state is determined during the screening procedure, using the Structured Clinical Interview for DSM Disorders (SCID), administered by one of the research team (who has been trained in the SCID use). The majority of study activities occur within a short window following the screening appointment and euthymic mood state is assumed at these appointments. Participants are instructed to inform the study team if they experience a mood episode at any point during their participation. Eligibility criteria, including mood symptoms, are assessed prior to all study visits.  \n<b>Reviewer Comment:<\/b> 5.&nbsp;Table 1. To facilitate understanding of Table 1 and the manuscript, I suggest that each assessment item be numbered to match the manuscript.  A) Thank you for this suggestion \u2013 we will amend the manuscript accordingly.  \n<b>Reviewer Comment:<\/b> 6.&nbsp;Page 15. Regarding the AX3 actigraphy device (Axivity, UK) and ActLumus light logger (Condor Instruments, Brazil), are these devices validated in the previous studies? If so, please add the references.&nbsp;  A)&nbsp;&nbsp;AX3 device has been validated in several adult populations for sleep and activity measures. ActLumus device has not yet been clinically validated. We will amend the manuscript accordingly to include references regarding the AX3 validation studies.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-64\/v2#referee-comment-5673","order":1,"name":"referee-comment-5673","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.22755.r76485, Karen Hallam, RMIT University, Melbourne, Victoria, 06 May 2024, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-64\/v1#referee-response-76485","order":2,"name":"referee-response-76485","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Amber Roguski<\/b>; \n<i>Posted: 01 Oct 2024<\/i>; We thank the reviewer for their thoughtful and comprehensive review of the HELIOS-BD protocol, and for their fundamental contributions to the field. Our responses are as follows, and we respond specifically to the below points for clarification or to indicate an update to the manuscript.  1. It is worth noting that the authors have not included some of our previous research in healthy volunteers showing a direct effect of lithium carbonate on reducing melatonin sensitivity to light in health volunteers, a finding that implies one potential physiological impact of lithium that may be involved in its management of bipolar disorders (see Hallam et al, 2005(Ref 2)). The protocol introduction has been updated to include this study, which provides important evidence for a role for lithium is regulation of circadian and melatonergic signalling. Thank you for highlighting this oversight.  2. In terms of measurement tools, confirmation of their diagnosis outside of clinical interview seems to have been excluded. It would be suggested that a formal screening questionnaire (e.g. the SCID) is utilised to standardise the assessment process.&nbsp; All potential participants with bipolar have their bipolar diagnosis confirmed by a psychiatrist during the screening appointment using the SCID. The responses to all SCID questions are stored for later analysis, for example, to stratify participants according to bipolar Type and polarity of symptoms (as suggested by the reviewer).  3. Notably, when assessing lifestyle factors, the team may want to investigate caffeine use (not covered in the AUDIT), which falls outside the AUDIT but has a clear impact on sleep quality for many people and potentially populations with BPAD (see Frigerio S,et.al., 2021(Ref 1)). It would also be logical to screen for other substance use. Caffeine use is not covered during the screening appointment, but we do gain detailed insight into caffeine consumption during the Part A procedure when participants fill out a consensus sleep diary for 12 days. This asks for details relating to consumption of caffeine, alcohol and medications. During the screening appointment, all potential participants are questioned relating to their alcohol and substance use and are not eligible to participate in the study if harmful or dependent use is indicated.  4. In relation to screening, it would typically be expected that the investigators would assess manic and\/or hypomanic symptoms at the time of testing and study inclusion. -&gt; Euthymic mood state is determined during the screening procedure, using the Structured Clinical Interview for DSM Disorders (SCID), administered by one of the research team (who has been trained in the SCID use). The majority of study activities occur within a short window following the screening appointment and euthymic mood state is assumed at these appointments. Participants are instructed to inform the study team if they experience a mood episode at any point during their participation. Eligibility criteria, including mood symptoms, are assessed by trained members of the research team prior to all study visits. &nbsp;  5. I am unsure of why the detailed ocular investigations follow the overnight melatonin measurement. It would make more sense for these tests to be conducted first to ensure the individual is appropriate for the study as any deficits in these measures may impact the participants results. The naming of the Part A, B and C appointments does not reflect their ordering in practice. Typically, participants attend the Baseline appointment and then their first Part C (retinal imaging) appointment in quick succession. We can therefore very quickly identify any previously undiscovered ocular issues in a timeframe very close to the enrolment of the participant. Appropriate action can then be taken (e.g. exclusion of the participant from further study activities). The Part A and Part B appointments are scheduled in the following months according to availability of the participant and the research team. Only Part C 9- and 18-month follow-up appointments must be scheduled within a strict timeframe \u2013 the remaining appointments are flexible in their scheduling.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-64\/v2#referee-comment-5836","order":3,"name":"referee-comment-5836","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [226787]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}