Large Individual Differences in Functional Connectivity in the Context of Major Depression and Antidepressant Pharmacotherapy
Authors: Wijk Gwen van der , Zamyadi Mojdeh , Bray Signe , Hassel Stefanie , Arnott Stephen R. , Frey Benicio N. , Kennedy Sidney H. , Davis Andrew D. , Hall Geoffrey B. , Lam Raymond W. , Milev Roumen , Müller Daniel J. , Parikh Sagar , Soares Claudio , Macqueen Glenda M. , Strother Stephen C. , Protzner Andrea B. 
Published: October 2023

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.

Significance statement

Studies on major depression often investigate differences in brain function between groups (e.g., those with/without a diagnosis) with the aim of better understanding this prevalent condition. Our study shows that group differences only tell part of the story, by highlighting strong common and individually unique features of brain network organization, relative to surprisingly subtle features of diagnosis and treatment success. From the overall explained variation in brain connectivity, about 50% was shared across everyone, while another 45% was unique to individuals. Only ∼5% could be attributed to diagnosis, treatment success and biological sex differences. Our results suggest that examining individual differences, and their potential clinical relevance, alongside group differences may bring us closer to improving clinical outcomes for major depression.

Trial registration

ClinicalTrials.gov:NCT01655706.