Discussion
depression, psychiatric, depressed
INFLAMMATION, DISORDERS
In the present study, we found an association between change in DTI-MD (∆-MD), a putative marker of neuroplasticity, and treatment response to ketamine in a sample of patients with depression. Reductions in MD scores in left BA10 and left amygdala, representing putative increased plasticity in these regions, predicted greater improvement in depression scores specifically in patients receiving ketamine. In right BA10, decreased MD scores predicted greater improvement in depression scores, independent of group (as reflected in the lack of a significant group * ∆-MD interaction effect). In both right and left hippocampus, the results were paradoxically in the opposite direction, with higher ∆-MD scores predicting greater improvement in clinician-rated depression scores in subjects receiving ketamine. However, there was no similar interaction between ∆-MD and group in predicting self-reported depression scores in either left or right hippocampus. Lastly, we found no significant effect of ∆-MD on depression scores in vACC or right amygdala. These findings were not appreciably changed in sensitivity analyses that included covariates in the statistical models, including concomitant psychiatric medication burden, level of treatment resistance, and baseline DTI-MD values (Table To our knowledge, this is the first placebo-controlled human study to investigate the association between a structural marker of acute neuroplasticity in depression-relevant brain regions and treatment response to ketamine, providing a first attempt to translate animal neuroscience findings, which have widely implicated synaptogenic mechanisms of action, back to the clinic. The regions in which increased plasticity predicted change in depression scores are right and left BA10 and left amygdala. Activity in these regions has been shown to be altered in depressed subjects, with studies of BA10 (and nearby related PFC regions) showing hyperactivation to reward-related cues and hypoactivation to negative affective cues (e.g., negatively valanced faces) in depressed subjects relative to controls [The structural mechanisms that underlie the functional changes in BA10 and left amygdala described above are unknown, but likely involve remodeling at the circuit, cellular, and/or synaptic level. This type of remodeling alters brain microstructure, leading to a change in the diffusion properties of water within this region (i.e., diffusion is restricted), resulting in a decrease in MD that reflects increased neuroplasticity [While in left BA10 there was a significant ∆-MD × group interaction effect, there was no similar interaction effect in the right BA10. This could indicate that plasticity in this region may play a larger role in the non-specific antidepressant effects that are common between the ketamine and placebo control groups, such as those associated with the infusion/research protocol, including the formation of therapeutic relationships, being in a therapeutic environment, positive feelings of helping others by contributing to research, and expectation of improvement.In contrast to the results seen in BA10 and left amygdala, which conformed to expectations based on the animal literature, in both the left and right hippocampus there was a significant effect in the opposite direction, with increased MD being associated with improved clinician-rated depression scores in the ketamine group. Unlike the majority of other findings we report, which were largely robust across both clinician- and self-rated depression symptoms (e.g., Fig. Finally, we did not observe any relationships between clinical outcomes and ∆-MD in two other regions included in analyses: right amygdala and vACC. Relative to the other regions under examination, the specific neural processes captured via DTI-MD within these two regions may play a less foundational role in ketamine’s rapid antidepressant effects; although we cannot rule out other possible explanations, such as measurement error, insufficient sample size, and other contributors to Type II error.Our data have clinical implications for the use of ketamine for depression. The plasticity induced by ketamine seems to persist, at least out to 24-h post-infusion, and potentially well beyond this. We can take advantage of this period of increased plasticity to augment the antidepressant effects of ketamine by combining it with other therapies, such as cognitive training. Indeed, in the primary outcome for this clinical trial, we previously reported that Automated Self-Association Training—a novel, low-cost, brief, computer-based intervention—extended the rapid antidepressant effect of a single ketamine infusion for at least 30 days [There are some limitations to the current study. Our measure of acute neuroplasticity, ∆-MD, is by necessity an indirect measure. While the previous studies using this metric as a measure of acute plasticity were investigating changes in hippocampal MD following learning, we are using it as a proxy for neuroplasticity in the context of treatment response for psychiatric disorders. Other factors that affect the diffusion of water, such as inflammation, could serve as confounds for our interpretation. The study was also limited by sample size, with 31 vehicle and 67 ketamine subjects, which is a subset of the whole clinical trial, and was likely underpowered to detect some interaction effects suggested by visual plots (Fig. 