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Abstract:
Background: Sub–anesthetic ketamine elicits rapid antidepressant response in patients and animal depression models (ADM), via modulation of glutamatergic system and increased synaptic plasticity [1]. Specifically, 24 h after infusion, ketamine induces changes in glutamine–glutamate cycling in pregenual anterior cingulate cortex (pgACC) in healthy controls (HC) [2]. Microtubules are essential for neural plasticity and post–translational modifications (PMTs) on α–tubulin are considered markers of microtubule dynamics [3]. Acetylation of α-tubulin is a marker of microtubule stability, and is altered in ADMs [4]. Exact
time courses of peripheral biomarkers and a meaningful prediction of ketamine response has not been fully established. Dissociative side–effects were considered to predict efficacy, but results were so far inconsistent. Therefore, we examined potential peripheral markers of tubulin dynamics and well–established changes in
glutamatergic system 24 h after infusion. Moreover, we investigated associations to acute dissociative symptoms.
Methods: In a placebo–controlled study 81 healthy controls
received 50 ml of 0.9 saline or 0.5 mg/kg of ketamine racemate over 40 min. At baseline and 24 h post–infusion, glutamate levels (Glu) were assessed in pgACC using magnetic resonance spectroscopy (MRS) in 7T, and blood plasma samples were collected. The dissociative side effects were evaluated using CADSS right after the infusion. MRS data were processed with LCModel, Glu was normalized to creatine, and grey matter (GM) partial volume was calculated. Plasma samples were prepared and analyzed by infrared western blotting. Acetylated-α-Tubulin (Acet–Tub) (Sigma) and Transferrin (TRF) (Abcam) expression was analyzed. Duplicates were averaged and Ace–Tub/TRF was normalized.
RmANOCOVA tested Glu and Ace–Tub/TRF change, with treatment, sex as factors, and age, BMI, (GM) as covariates of nuisance. The relationship between relative changes and CADSS was assessed with non–parametric partial correlations in ketamine group. Statistical analysis was done in IBM SPSS24.
Results: Ketamine effect was present in both Glu (time–by–
treatment F1,66 = 4.21, p = 0.044) and Ace-Tub/TRF (time–by–
treatment–by–sex F1,65 = 5.39, p = 0.023), where a decrease in pgACC Glu and an increase in Ace–Tub/TRF was observed.
Markers of sustained effect were negatively associated with
each other only in the ketamine group (rho(25) = –0.61, p = 0.001; control– rho(27) = 0.25, p = 0.20). Marker of acute effect CADSS trend–wise positively correlated to Ace–Tub/TRF (rho(30) = 0.33, p = 0.06) in the ketamine group, but not with pgACC Glu (rho(30) = −0.23, p = 0.21).
Conclusion: Results confirm effects of single sub–anesthetic
dose of ketamine on glutamate levels 24 h after infusion in the pgACC, a region important for affect processing and neuronal mechanisms of depression. In parallel, it was shown that Acet–Tub measured in plasma increases, suggesting peripheral microtubule stabilization which may be reflected centrally. Thus, the neuronal representation of ketamine was negatively associated with Acet–Tub/TRF, indicating similar time–frame of plasticity processes in brain and blood. Interestingly only Acet–Tub/TRF was positively associated with degree of acute dissociative symptoms. The next step is to differentiate between parameters (i.e. psychomimetic, anti–inflammatory) and determine their relevance to the true potential of ketamine as an antidepressant treatment.
