The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

Abstract

As ketamine is increasingly used as an effective antidepressant with rapid action, sustaining its short-lived efficacy over a longer period of time using a schedule of repeated injections appears as an option. An open question is whether repeated and single administrations would affect convergent neurocircuits. We used a combination of one of the most robust animal models of depression with high-field neuroimaging to perform a whole-brain delineation of functional mechanisms underlying ketamine's effects. Rats from two genetic strains, depressive-like and resilient, received seven treatments of 10 mg/kg S-ketamine (N = 14 depressive-like, N = 11 resilient) or placebo (N = 12 depressive-like, N = 10 resilient) and underwent resting-state functional magnetic resonance imaging. Using graph theoretical models of brain networks, we compared effects of repeated ketamine with those of single administration from a separate dataset of our previous study. Compared to single treatment, repeated ketamine evoked strain-specific brain network randomization, resembling characteristics of the depressive-like strain and patients. Several affected regions belonged to the auditory, visual, and motor circuitry, hinting at possible cumulative side effects. Finally, when compared to saline, repeated ketamine affected only a few local topological properties and had no effects on global properties. In combination with the lack of clear differences compared to placebo, our findings point toward an inefficacy of ketamine's long-term administration on brain topology, making questionable the postulated effect of repeated administration and being consistent with the recently reported absence of repeated ketamine's antidepressant efficacy in several placebo-controlled studies.

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

“…Image preprocessing was performed as in our previous studies [ 30 , 31 ] and included the following steps: (a) correction for magnetic field inhomogeneities and movement (“realign & unwarp”, SPM12); (b) regressing respiratory and cardiac signals (Aztec software) [ 32 ]; (c) slice-timing correction (SPM12); (d) coregistration and spatial normalization to SIGMA atlas template [ 28 ] using DARTEL-based flow fields (obtained from the 3D image coregistration and normalization) (SPM12); (e) regressing movement parameters and cerebrospinal fluid signal (FSL, version 5 http://www.fmrib.ox.ac.uk/fsl ); (f) identification of motion-affected frames (Fig. S2 ) based on DVARS decomposition [ 33 ] and removal, based on p values instead of an arbitrary threshold, with subsequent scrubbing (spline-curve interpolation) [ 34 ]; (g) band-pass filtering (0.01–0.1 Hz) (Analysis of Functional NeuroImages, version 2) [ 35 ].…”

Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One?

“…To better compare a single dose with repeated dosing, future studies should keep all other experimental variables the same, including the time lag between the last (or only) dose of ketamine and the start of the FST or other behavioral tests [sucrose preference, novelty suppressed feeding, splash; as well as open field (to test generalized hyperactivity)]. It should be noted that in a recent study using rats selectively bred for depressive-like behavior, repeated ketamine (10 mg/kg/day for 7 consecutive days) did not produce favorable brain network topological effects relative to vehicle or a single ketamine injection, calling into question the general approach of using repeated ketamine in this animal model ( 17 ).…”

“…This ongoing debate includes investigating the efficacy of the R enantiomer of ketamine in a rat learned helplessness model ( 15 ), and also potentially dose-dependent sex differences in response to ketamine ( 16 ). It is not clear at this time whether the molecular or circuit-based mechanisms of single dose ketamine differ just in magnitude or instead qualitatively from those of repeated administration, but qualitative differences are possible ( 17 ).…”

Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review

“…Moreover, another relevant question is how ESK should be discontinued. Even though ESK was safe and well tolerated even in the long term, potential abuse and effects on cognition should be taken into account, especially in the case of prolonged administration [15,35,36]. Another issue to be considered is the uncertain effect of ESK on suicidal ideation in the long term.…”