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Antidepressant-related microstructural changes in the external capsule

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Several magnetic resonance imaging (MRI) studies have reported that antidepressant medications are strongly linked to brain microstructural alterations. Notably, external capsule alterations have been reported to be a biological marker for therapeutic response. However, prior studies did not investigate whether a change in the neurite density or directional coherence of white matter (WM) fibers underlies the observed microstructural alterations. This MRI-based case–control study examined the relationship between patients’ current use of antidepressant medications and advanced measurements of external capsule WM microstructure derived from multishell diffusion imaging using neurite orientation dispersion and density imaging (NODDI). The study compared a group of thirty-five participants who were taking antidepressant medications comprising selective serotonin reuptake inhibitors (SSRIs) (n = 25) and serotonin and norepinephrine reuptake inhibitors (SNRIs) with a control group of thirty-five individuals matched in terms of age, sex, race, and atherosclerotic cardiovascular risk factors. All participants were selected from the Dallas Heart Study phase 2, a multi-ethnic, population-based cohort study. A series of multiple linear regression analyses were conducted to predict microstructural characteristics of the bilateral external capsule using age, sex, and antidepressant medications as predictor variables. There was significantly reduced neurite density in the bilateral external capsules of patients taking SSRIs. Increased orientation dispersion in the external capsule was predominantly seen in patients taking SNRIs. Our findings suggest an association between specific external capsule microstructural changes and antidepressant medications, including reduced neurite density for SSRIs and increased orientation dispersion for SNRIs.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.



Magnetic resonance imaging


Diffusion tensor imaging


Neurite orientation dispersion and density imaging


Neurite density


Orientation dispersion


Fractional anisotropy


Mean diffusivity


White matter


Selective serotonin reuptake inhibitors


Dallas Hearts and Minds Study


Inferior fronto-occipital fasciculus


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Dr. Kerpel led this study without any financial support or grants.

The DHS was supported by grants from the Donald W. Reynolds Foundation and the National Center for Advancing Translational Sciences (UL1TR001105). The funders had no role in the design and conduct of the study or in the collection, management, analysis, and interpretation of the data.

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Authors and Affiliations



Ariel Kerpel – conception and study design, data collection, statistical analysis, interpretation of results, draft of manuscript.

Elizabeth Davenport – data acquisition, study design, interpretation of results, revision of manuscript.

Amy L. Proskovec – data collection, revision of manuscript.

Yin Xi—statistical analysis.

Jarett D. Berry – revision of manuscript.

Zerrin Yetkin – revision of manuscript.

Joseph Maldjian – revision of manuscript.

Fang F. Yu – conception and study design, statistical analysis, interpretation of results.

Corresponding author

Correspondence to Ariel Kerpel.

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Ethics approval

The study was approved by the Institutional Review Board (IRB) of The University of Texas Southwestern Medical Center, Dallas, Texas. The study has been conducted in accordance with the Declaration of Helsinki.

Consent to participate

The DHS subjects provided written informed consent.

Competing interests

The authors declare no competing interests.

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Supplementary file1 (DOCX 28 KB)

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Kerpel, A., Davenport, E., Proskovec, A.L. et al. Antidepressant-related microstructural changes in the external capsule. Brain Imaging and Behavior (2024).

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