Major depressive disorder (MDD) is a significant public health concern, characterized by deficits in neuroplasticity. These deficits manifest in various ways, including decreased long-term potentiation, reduced synaptic protein expression, impaired BDNF and mTOR signaling, and alterations in synaptogenesis and neurogenesis. These impairments lead to dysfunction within corticolimbic circuits. Effective antidepressant therapies reverse many of these neuroplasticity deficits, supporting the hypothesis that neuroplasticity impairments are a core mechanism in MDD. While functional neuroplasticity cannot be directly measured in living humans, post-mortem studies and neuroimaging reveal structural and functional deficits in depressed individuals, including gray matter volume loss and hypofunction in key brain regions. Ketamine, a dissociative anesthetic, has shown rapid and robust antidepressant effects, even in treatment-resistant patients. The mechanisms underlying ketamine's antidepressant effects are not fully understood, but they are hypothesized to involve rapid enhancement of neuroplasticity. This study aimed to quantify gray matter microstructural changes on a 24-hour timescale in key brain regions implicated in neuroplasticity enhancement following ketamine in animal models, and to investigate the relationship between these changes and clinical response to ketamine in patients with treatment-resistant depression.

The introduction extensively reviews the existing literature on neuroplasticity deficits in MDD, citing evidence from rodent models and human studies. It highlights the role of various factors such as long-term potentiation, synaptic protein expression, BDNF and mTOR signaling, synaptogenesis, and neurogenesis in the pathophysiology of depression. The literature also supports the idea that effective antidepressant treatments reverse these deficits, strengthening the link between neuroplasticity and MDD. The review then focuses on ketamine's rapid antidepressant effects and its potential mechanism of action involving neuroplasticity enhancement, setting the stage for the current study's investigation into the relationship between ketamine's effects and structural neuroplasticity changes.

Ninety-eight adults with unipolar depression who had failed at least one antidepressant medication were randomly assigned (2:1 ratio) to receive a single intravenous infusion of ketamine (0.5 mg/kg) or a vehicle (saline). Participants underwent diffusion tensor imaging (DTI) assessments at baseline and 24 hours post-infusion. DTI mean diffusivity (MD), a marker of microstructural neuroplasticity in gray matter, was calculated for seven regions of interest (left and right BA10, amygdala, and hippocampus; and ventral anterior cingulate cortex (vACC)). Clinical response was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). The researchers compared DTI-MD changes between groups and examined the association between individual differences in DTI-MD change and clinical response. Statistical analyses included two-tailed independent sample t-tests and multiple linear regressions to assess interaction effects between ketamine/saline and DTI-MD changes on depression scores. A sensitivity analysis was conducted to assess the relationships between neuroplasticity and clinical improvement, considering covariates such as medication burden and treatment resistance.

Ketamine significantly improved MADRS scores 24 hours post-infusion in the full sample and the DTI subsample. However, there was no significant effect on QIDS-SR scores in the DTI subsample. Ketamine had no significant main effect on Δ-MD values. Linear regression analyses revealed significant interactions between Δ-MD and group in predicting QIDS and MADRS scores. Specifically, reductions in MD (putative increased plasticity) in the left BA10 and left amygdala predicted greater improvement in depression scores in the ketamine group. In the right BA10, decreased MD predicted greater improvement regardless of group. Paradoxically, in the left and right hippocampus, increased MD was associated with improved MADRS scores in the ketamine group. Sensitivity analyses, including covariates, did not substantially alter these findings. There were no significant relationships between clinical outcomes and Δ-MD in the right amygdala or vACC.

The findings provide evidence for an association between acute neuroplasticity changes and treatment response to ketamine in depression. Reductions in MD in the left BA10 and left amygdala, suggesting increased plasticity, predicted greater improvement in depression scores, particularly in the ketamine group. This aligns with preclinical findings implicating these regions in depression and the effects of ketamine. The paradoxical finding in the hippocampus requires further investigation but may relate to ketamine-induced synaptic pruning or other factors such as increased cerebral blood flow. The lack of significant effects in the right amygdala and vACC might be due to their less central role in ketamine's rapid antidepressant effects or methodological limitations. The study's results highlight the potential for combining ketamine with other therapies to enhance its effects and the importance of considering the post-treatment environment to optimize treatment outcomes.

This study demonstrates an association between ketamine-induced neuroplasticity changes and its antidepressant effects in treatment-resistant depression. Changes in MD in several brain regions predicted improvement in depression scores, although effect sizes were relatively small. These findings support the hypothesis that ketamine's antidepressant effects are mediated, at least in part, by rapid increases in neuroplasticity. Future research should explore the long-term effects of ketamine on neuroplasticity and investigate potential synergistic therapies.

The study's limitations include the measurement of acute neuroplasticity only, the use of MD as a proxy for neuroplasticity, the potential for confounding factors influencing water diffusion, the underpowered nature of the study for detecting interaction effects, and the heterogeneity of responses in psychiatric illnesses. The relatively small effect sizes also limit the generalizability of the findings. The lack of assessment of ketamine's impact on white matter microstructure represents another limitation.