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Sex matters: acute functional connectivity changes as markers of remission in late-life depression differ by sex

Molecular Psychiatry volume 28, pages 5228–5236 (2023)Cite this article

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Abstract

The efficacy of antidepressant treatment in late-life is modest, a problem magnified by an aging population and increased prevalence of depression. Understanding the neurobiological mechanisms of treatment response in late-life depression (LLD) is imperative. Despite established sex differences in depression and neural circuits, sex differences associated with fMRI markers of antidepressant treatment response are underexplored. In this analysis, we assess the role of sex on the relationship of acute functional connectivity changes with treatment response in LLD. Resting state fMRI scans were collected at baseline and day one of SSRI/SNRI treatment for 80 LLD participants. One-day changes in functional connectivity (differential connectivity) were related to remission status after 12 weeks. Sex differences in differential connectivity profiles that distinguished remitters from non-remitters were assessed. A random forest classifier was used to predict the remission status with models containing various combinations of demographic, clinical, symptomatological, and connectivity measures. Model performance was assessed with area under the curve, and variable importance was assessed with permutation importance. The differential connectivity profile associated with remission status differed significantly by sex. We observed evidence for a difference in one-day connectivity changes between remitters and non-remitters in males but not females. Additionally, prediction of remission was significantly improved in male-only and female-only models over pooled models. Predictions of treatment outcome based on early changes in functional connectivity show marked differences between sexes and should be considered in future MR-based treatment decision-making algorithms.

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Fig. 1: CONSORT diagrams for the Circuits2 and NEMO studies.
Fig. 2: Study design and analysis flow chart.
Fig. 3: Regional differential connectivity summary differences between remitters and non-remitters according to sex.
Fig. 4: Prediction performance of models to predict remitter status.
Fig. 5: Differential connectivity importance for prediction of remission.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The code used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was funded by NIMH grants R01 MH076079, R01 MH108509, R01 MH121619, K01 MH122741, and T32 MH019986. The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

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  1. These authors contributed equally: James D. Wilson, Andrew R. Gerlach.

Authors and Affiliations

  1. Department of Mathematics and Statistics, University of San Francisco, San Francisco, CA, USA

    James D. Wilson

  2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Andrew R. Gerlach, Helmet T. Karim, Howard J. Aizenstein & Carmen Andreescu

  3. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Helmet T. Karim & Howard J. Aizenstein

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Contributions

JDW developed and implemented the analytic approach and was a major contributor in writing the manuscript. ARG processed the data, guided the analytic approach, interpreted results, and was the primary contributor in writing the manuscript. HTK guided the processing, analysis, and interpretation. HJA designed the study and guided the analysis and interpretation. CA designed the study, guided analysis and interpretation, and was a major contributor in writing the manuscript.

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Correspondence to Carmen Andreescu.

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Wilson, J.D., Gerlach, A.R., Karim, H.T. et al. Sex matters: acute functional connectivity changes as markers of remission in late-life depression differ by sex. Mol Psychiatry 28, 5228–5236 (2023). https://doi.org/10.1038/s41380-023-02158-0

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