Changes in white matter microstructure following serial ketamine infusions in treatment resistant depression

Abstract

Ketamine produces fast‐acting antidepressant effects in treatment resistant depression (TRD). Though prior studies report ketamine‐related changes in brain activity in TRD, understanding of ketamine's effect on white matter (WM) microstructure remains limited. We thus sought to examine WM neuroplasticity and associated clinical improvements following serial ketamine infusion (SKI) in TRD. TRD patients ( N = 57, 49.12% female, mean age: 39.9) received four intravenous ketamine infusions (0.5 mg/kg) 2–3 days apart. Diffusion‐weighted scans and clinical assessments (Hamilton Depression Rating Scale [HDRS‐17]; Snaith Hamilton Pleasure Scale [SHAPS]) were collected at baseline and 24‐h after SKI. WM measures including the neurite density index (NDI) and orientation dispersion index (ODI) from the neurite orientation dispersion and density imaging (NODDI) model, and fractional anisotropy (FA) from the diffusion tensor model were compared voxelwise pre‐ to post‐SKI after using Tract‐Based Spatial Statistics workflows to align WM tracts across subjects/time. Correlations between change in WM metrics and clinical measures were subsequently assessed. Following SKI, patients showed significant improvements in HDRS‐17 ( p ‐value = 1.8 E‐17) and SHAPS ( p ‐value = 1.97 E‐10). NDI significantly decreased in occipitotemporal WM pathways ( p < .05, FWER/TFCE corrected). ΔSHAPS significantly correlated with ΔNDI in the left internal capsule and left superior longitudinal fasciculus ( r = −0.614, p ‐value = 6.24E‐09). No significant changes in ODI or FA were observed. SKI leads to significant changes in the microstructural features of neurites within occipitotemporal tracts, and changes in neurite density within tracts connecting the basal ganglia, thalamus, and cortex relate to improvements in anhedonia. NODDI may be more sensitive for detecting ketamine‐induced WM changes than DTI.

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression

“…Lastly, there was no main effect of ketamine on ∆-MD, as we might predict if it were the sole mediator of treatment response, indicating that numerous other factors are likely involved in the antidepressant effects of ketamine among human patients. Such factors could include additional neuroplasticity mechanisms, such as the impact of ketamine on white matter microstructure and tractography [ 62 , 63 ] which was not assessed in the current study due to scanner sequence timing constraints and lack of a priori hypotheses regarding white matter effects; as well as a wide range of factors beyond neuroplasticity per se.…”

Hippocampal subfield volumes in treatment resistant depression and serial ketamine treatment

“…Patients who met DSM-5 diagnostic criteria for MDD ( 25 ) and experienced inadequate response to 2 or more prior antidepressant trials of sufficient dose and duration and had been continuously depressed for at least 6 months were recruited. Further details on inclusion and exclusion criteria have been previously described ( 22 , 26 , 27 ). Briefly, inclusion criteria entailed men and women between the ages of 20–64, pre-treatment moderate to severe depressive symptoms (17-item Hamilton Depression Rating Scale (HDRS) total score ≥ 17), stable antidepressant or mood stabilizer use for 6 or more weeks prior to study participation.…”

Ketamine treatment modulates habenular and nucleus accumbens static and dynamic functional connectivity in major depression

“…However, alterations in visual networks have also been associated with depression 79,80 . Further, three studies from our own group employing different imaging modalities and including an overlapping TRD sample have reported ketamine-related modulation of visual areas, including changes in BOLD activation during a response inhibition task 81 , increases in cerebral blood flow 82 , and changes in white matter microstructure within occipital white matter pathways 83 . Notably, one of the few published studies investigating the effects of ketamine on habenula FC found that increases in sFC between the habenula and occipital pole and lateral visual cortex following a single ketamine infusion significantly correlated with improvements in subjectively rated depressive symptoms 50 .…”

“…However, alterations in visual networks have also been associated with depression 79,80 . Further, three studies from our own group employing different imaging modalities and including an overlapping TRD sample have reported ketamine-related modulation of visual areas, including changes in BOLD activation during a response inhibition task 81 , increases in cerebral blood flow 82 , and changes in white matter microstructure within occipital white matter pathways 83 .…”