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

Abstract

Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016–0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032–0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.

Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome

“…However, most of these genes returned to baseline expression levels within one day, providing the opportunity to examine acute and persistent effects of ketamine on gene expression. The acute findings are in line with previous research highlighting the acute and short-lasting effects of ketamine on neuronal activity and synaptic plasticity (Kim, et al, 2022;Chen, et al, 2021;Li, et al, 2010;Kopelman, et al, 2023;Grieco, et al, 2021). The rapid normalization of gene expression suggests that ketamine-induced alterations in transcription are part of a dynamic and regulated process, potentially involving the transient modulation of signaling pathways or feedback mechanisms.…”

“…This observation aligns with independent investigations that also show limited alterations in ASDrelated gene expression following ketamine administration (Ho, et al, 2019;Cathomas, et al 2021). As such, clinical benefits observed with ketamine are likely mediated by broader downstream effects of ketamine, such as modulation of synaptic plasticity, glutamate signaling, or neuroinflammatory responses (Nugent, et al, 2019;Kopelman, et al, 2023;Abdallah, et al, 2018;Li, et al, 2020;Chen, et al, 2021;Grieco, et al, 2021;.…”

Multimodal structural neuroimaging data unveil data-driven subtypes of treatment-resistant depression

“…perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 18, 2023. ; https://doi.org/10.1101/2023.09.12.23295423 doi: medRxiv preprint 13 neuroplastic changes, such as electroconvulsive therapy (70)(71)(72)(73), repetitive transcranial magnetic stimulation (74,75), deep brain stimulation (76,77), and ketamine (78)(79)(80), whereas treatments targeting the immunemetabolic pathways, such as physical exercise, diet or anti-inflammatory treatments, may be also useful in alleviating the energy-related symptoms (81)(82)(83). Furthermore, considering that the high-TRD cluster was also associated with high scores for CTQ, this group may benefit from adjunctive psychotherapeutic interventions focused on trauma (84,85).…”

Hippocampal and parahippocampal volume and function predict antidepressant response in patients with major depression: A multimodal neuroimaging study

“…However, in recent years, studies investigating brain correlates of treatments with different mechanisms of action such as ketamine are beginning to emerge. Interestingly, they seem to again identify the hippocampus as a key region in affecting response, albeit with somewhat conflicting results: indeed if on the one hand Ketamine was found to be more effective in patients with relatively smaller left hippocampus (Abdallah et al, 2015), at the same time ketamine treatment was associated with increases in hippocampal volumes (Höflich et al, 2021) and mean diffusivity (Kopelman et al, 2023).…”