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

Depression is associated with deficits in neuroplasticity across animal and human studies, and these impairments are thought to contribute to maladaptive cognitive and affective responses. In rodents, stress-induced depression-like behaviours are accompanied by reductions in synaptic markers, impaired BDNF and mTOR signalling, loss of synapses and dendritic atrophy; many effective antidepressant interventions reverse these deficits. Ketamine has shown rapid antidepressant effects in humans and robust synaptogenic effects in animal models, but direct evidence linking acute structural neuroplasticity in human brain regions to ketamine’s clinical effects has been lacking. The researchers set out to test whether rapid, region-specific changes in a diffusion MRI-derived measure (mean diffusivity, MD) — interpreted as a proxy for microstructural neuroplasticity — relate to 24-h clinical response after a single intravenous ketamine infusion (0.5 mg/kg) versus saline. They measured MD before and 24-h after infusion in seven a priori regions implicated in depression and ketamine action (left/right BA10, left/right amygdala, left/right hippocampus, and ventral anterior cingulate cortex), and hypothesised that larger region-specific decreases in MD (reflecting increased plasticity) would predict larger clinical improvements, particularly in the ketamine group.

This analysis used a subset of participants from clinical trial NCT03237286. The full trial randomised 154 adults (age 18–60) with moderate-to-severe unipolar depression (MADRS ≥25) and at least one failed adequate antidepressant trial to ketamine or saline in a 2:1 ratio. The current neuroimaging analysis included 98 subjects with usable diffusion tensor imaging (DTI) at baseline and 24 h post-infusion: 67 randomised to ketamine and 31 to vehicle (saline). The primary clinical measures were clinician-rated MADRS and self-rated QIDS-SR assessed pre-infusion and 24 h post-infusion. Interventions comprised a single 40-min infusion of ketamine (0.5 mg/kg) or matched saline vehicle, administered under blinded conditions with clinical monitoring in a hospital setting; adverse-event monitoring continued for 4 h post-infusion. Current medications and treatment history were recorded and medication burden calculated via ATHF. The study was performed at the University of Pittsburgh with institutional approval and informed consent. Neuroimaging: DTI data were acquired on a 3T Siemens Prisma using multiband sequences (scanner details in extraction are limited). Standard DTI preprocessing in FSL included correction for geometric distortions (topup), motion (mcflirt), eddy currents (eddy), linear co-registration of baseline and 24-h scans, nonlinear warping to MNI space, and tensor fitting to produce voxel-wise mean diffusivity (MD) maps. Anatomical ROI masks from the MNI atlas were used to extract average MD in left/right BA10, left/right amygdala, left/right hippocampus, and ventral ACC (subgenual and perigenual). A change score Δ-MD was calculated as MDpre − MD24h, so that a higher Δ-MD corresponds to a larger decrease in MD (interpreted as greater plasticity/synaptogenesis). Extreme Δ-MD values were Winsorized prior to analysis. Statistical analysis used IBM SPSS. Two-tailed independent-sample t-tests examined main effects of group on clinical change and on Δ-MD. Multiple linear regression models predicted change in MADRS and QIDS-SR from Δ-MD, group (ketamine vs. vehicle), and their interaction to test whether relationships between Δ-MD and clinical improvement differed by infusion arm. Sensitivity analyses added covariates (baseline MD, level of treatment resistance, concurrent psychotropic medications). Exploratory outcomes for anxiety, positive affect and dissociation were reported elsewhere (supplement).

The imaging subset comprised 98 participants (67 ketamine, 31 vehicle). In the full clinical trial ketamine improved both MADRS and QIDS at 24 h. In the imaging subset, ketamine produced a significant improvement on clinician-rated MADRS at 24 h (t(96) = -3.01, p = 0.003) but did not significantly change QIDS-SR scores in this subset (t(95) = -1.10, p = 0.28). Ketamine produced no significant main effect on raw or Winsorized Δ-MD in any ROI. Regression analyses relating Δ-MD to clinical change identified region-specific patterns. Left BA10: there was a significant Δ-MD × group interaction for QIDS (β = 0.386, t(96) = 2.143, p = 0.035), indicating that decreases in MD (greater Δ-MD) predicted larger self-reported symptom improvement specifically in the ketamine arm. For MADRS there was a significant main effect of group (β = 0.314, t(96) = 3.207, p = 0.002) and a trend for the Δ-MD × group interaction (β = 0.308, t(96) = 1.760, p = 0.082), with greater clinician-rated improvement associated with decreased MD primarily in the ketamine group. Right BA10: reduced MD predicted greater improvement independent of group. For QIDS the main effect of Δ-MD was significant (β = 0.275, t(96) = 2.771, p = 0.007). For MADRS there were significant main effects of both Δ-MD (β = 0.196, t(96) = 2.019, p = 0.046) and group (β = 0.268, t(96) = 2.763, p = 0.007). No Δ-MD × group interactions reached significance in right BA10. Left amygdala: significant Δ-MD × group interactions were observed for both QIDS (β = 0.477, t(96) = 2.446, p = 0.016) and MADRS (β = 0.414, t(96) = 2.238, p = 0.028), indicating that decreased MD predicted greater improvement specifically in the ketamine group. Hippocampus findings were in the opposite direction for clinician-rated outcomes. Left hippocampus: a significant Δ-MD × group interaction for MADRS (β = -0.337, t(96) = -2.178, p = 0.032) indicated that, in the ketamine group, increased MD (smaller or negative Δ-MD) predicted greater clinician-rated improvement. No effects for QIDS were found in hippocampus. Right hippocampus: a significant main effect of group on MADRS was observed (β = 0.343, t(96) = 3.420, p = 0.001) and there was a trend for a Δ-MD × group interaction (β = -0.303, t(96) = -1.902, p = 0.060) mirroring the left hippocampus pattern. No significant main or interaction effects were found for right amygdala or ventral ACC. Sensitivity analyses adding baseline MD, treatment-resistance severity, or concurrent psychotropic medication burden as covariates produced minimal changes to the pattern and statistical significance of reported findings. The authors report effect sizes for the significant models were modest (R2 values between 0.05 and 0.18).

Bell and colleagues interpret their results as evidence that acute, region-specific microstructural changes measured by Δ-MD are associated with 24-h antidepressant response following ketamine. Key findings were that decreases in MD in left BA10 and left amygdala — interpreted as increased structural plasticity or synaptogenesis — predicted larger symptom improvements specifically in the ketamine-treated participants. Decreased MD in right BA10 predicted improvement regardless of infusion arm, suggesting that plasticity in that region may relate to non-specific components of improvement such as expectancy, clinical interaction or study context. In contrast, hippocampal findings were paradoxical: increased MD in left and right hippocampus was associated with greater clinician-rated improvement in the ketamine group. The authors note this direction is difficult to interpret; increased MD can reflect diverse processes (for example, changes in cerebral blood flow, tissue composition, or other microstructural factors) and may not straightforwardly index reduced plasticity. The authors position their findings as a first placebo-controlled human translation of animal work linking ketamine to rapid synaptogenesis in corticolimbic regions. They suggest that structural remodelling in BA10 and the left amygdala could underlie changes in emotional processing and behavioural output after ketamine (for example, reduced salience of negative stimuli), and that such structural changes might be leveraged therapeutically. Practically, they propose that a post-ketamine window of increased plasticity could be exploited by combining ketamine with behavioural or cognitive interventions to extend clinical benefit. Acknowledged limitations include the indirect nature of Δ-MD as a proxy for synaptogenesis (other processes such as inflammation or cerebral blood flow can affect MD), the modest sample size of the imaging subset (67 ketamine, 31 saline) which may limit power to detect interactions or main effects, and the absence of non-depressed control subjects to assess baseline differences or normalisation. The authors also note small effect sizes (R2 = 0.05–0.18), the lack of a main effect of ketamine on Δ-MD (meaning Δ-MD is unlikely to be the sole mediator of response), and the decision to limit analyses to seven a priori regions without adjustment for multiple comparisons within that set. They acknowledge unassessed factors (e.g. white matter microstructure) that could contribute to ketamine’s antidepressant effects. Overall, the authors present their findings as supportive but preliminary evidence that rapid structural plasticity measurable with DTI-MD relates to ketamine response and merits further investigation.

The authors conclude that a diffusion-MRI proxy for acute structural neuroplasticity was associated with clinical response to ketamine in several depression-relevant brain regions, supporting the hypothesis that ketamine’s rapid antidepressant effects are partly mediated by enhanced neuroplasticity and synaptogenic processes. They suggest these observations have implications for combining ketamine with other interventions during a putative post-infusion plastic window and for improving understanding of ketamine’s neurobiological mechanisms.