Large Individual Differences in Functional Connectivity in the Context of Major Depression and Antidepressant Pharmacotherapy

Clinical studies of major depression (MD) often examine differences between groups whilst ignoring within-group variation. However, inter-individual differences in brain function are increasingly recognised as important and may impact effect sizes related to group effects. Here, we examine the magnitude of individual differences in relation to group differences that are commonly investigated (e.g., related to MD diagnosis and treatment response). Functional MRI data from 107 participants (63 female, 44 male) were collected at baseline, 2 and 8 weeks during which patients received pharmacotherapy (escitalopram, N=68), and controls (N=39) received no intervention. The unique contributions of different sources of variation were examined by calculating how much variance in functional connectivity was shared across all participants and sessions, within/across groups (patients vs controls, responders vs non-responders, female vs male participants), recording sessions and individuals. Individual differences and common connectivity across groups, sessions and participants contributed most to the explained variance (>95% across analyses). Group differences related to MD diagnosis, treatment response and biological sex made significant but small contributions (0.3-1.2%). High individual variation was present in multimodal association areas, while low individual variation characterized primary sensorimotor regions. Group differences were much smaller than individual differences in the context of MD and its treatment. These results could be linked to the variable findings and difficulty translating research on MD to clinical practice. Future research should examine brain features with low and high individual variation in relation to psychiatric symptoms and treatment trajectories to explore the clinical relevance of the individual differences identified here. ### Competing Interest Statement Benicio N. Frey has received grant/research support from Alternative Funding Plan Innovations Award, Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Hamilton Health Sciences Foundation, J. P. Bickell Foundation, Ontario Brain Institute, Ontario Mental Health Foundation, Society for Women's Health Research, Teresa Cascioli Charitable Foundation, Eli Lilly and Pfizer, and has received consultant and/or speaker fees from AstraZeneca, Bristol-Myers Squibb, Canadian Psychiatric Association, CANMAT, Daiichi Sankyo, Lundbeck, Pfizer, Servier and Sunovion. Roumen V. Milev has received consulting and speaking honoraria from AbbVie, Allergan, Janssen, KYE, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI and OMHF. Sagar Parikh has been a consultant to Takeda, Bristol Myers Squibb, Lund- beck; has had a research contract with Assurex; has equity in Mensante. Raymond W. Lam has received speaker and consultant honoraria or research funds from AstraZeneca, Brain Canada, Bristol-Myers Squibb, the Canadian Institutes of Health Research (CIHR), the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Eli Lilly, Janssen, Lundbeck, Lundbeck Institute, Medscape, Otsuka, Pfizer, Servier, St. Jude Medical, Takeda, the University Health Network Foundation, Vancouver Coastal Health Research Institute, Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Healthy Minds Canada, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Unity Health, Viatris, and VGH-UBCH Foundation. Sidney H. Kennedy has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, CIHR, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, Sun Pharmaceuticals, and holds stock in Field Trip Health. Daniel J. Müller has received consulting and speaking honoraria from Lundbeck and Genomind. Dr Soares has received consulting and speaking honoraria from Pfizer, Otsuka, Bayer, Eisai and research grants from CAN-BIND, CIHR, OBI, and SEAMO. Stephen C Strother is a senior Scientific Advisor and shareholder in ADMdx, Inc., which receives NIH funding, and during the period of this research, he had research grants from Brain Canada, Canada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), and the Ontario Brain Institute in Canada. Other authors declare no competing financial interests. ### Clinical Trial NCT01655706 ### Clinical Protocols ### Funding Statement CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Additional funding is provided by the Canadian Institutes of Health Research (CIHR), Lundbeck, and Servier. Funding and/or in-kind support is also provided by the investigators' universities and academic institutions. All study medications are independently purchased at wholesale market values. We acknowledge support to Gwen van der Wijk in the form of a Mamdani Family Foundation Graduate Scholarship and Alberta Graduate Excellence Scholarship (AGES: International). The funders had no role in the design, analysis, interpretation, or publication of this study ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was obtained from all participating centres. The ethics committees include: UBC Clinical Research Ethics Board (Vancouver); UCA Conjoint Health Research Ethics Board (Calgary); University Health Network Research Ethics Board (Toronto); CAM Research Ethics Board (Toronto); Hamilton Integrated Research Ethics Board (Hamilton); and QNS Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (Kingston). The participants provided written, informed consent for all study procedures. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in this manuscript has been collected as part of the CAN-BIND initiative, an Integrated Discovery Program of the Ontario Brain Institute (OBI). OBI has released data from CAN-BIND's foundational study which aims to identify biomarkers that predict treatment response in people with depression. The dataset currently available on Brain-CODE includes baseline and longitudinal data from participant follow-up visits in weeks 2 to 8 of the study (Phase 1). All data have been standardized, cleaned and curated to maximize utility for analysis across different data modalities, and imaging data was converted to a BIDS-friendly naming convention. For access requirements, please visit OBI's Brain-CODE Neuroinformatics Platform (https://www.braincode.ca/) or email info@braininstitute.ca.