Abstract
Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine’s antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30 min and 48 h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine’s distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine’s dissociative and antidepressant properties. At 48 h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine’s procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine’s distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.
Highlights
Major depressive disorder (MDD) is a globally prevalent psychiatric illness with cognitive, affective, and somatic symptoms, including negative emotional states, cognitive impairments, anxiety, anergia, and anhedonia[1]
As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine’s procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine’s distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing
Recent evidence indicates that ketamine, an NMDA receptor antagonist with rapid antidepressant effects sustained for 7 days[4], has high potential to normalize disrupted network connectivity, proposing it as the mechanism of action[5]
Summary
Major depressive disorder (MDD) is a globally prevalent psychiatric illness with cognitive, affective, and somatic symptoms, including negative emotional states, cognitive impairments, anxiety, anergia, and anhedonia[1] These symptoms correlate with the aberrant connectivity in brain circuits, suggesting it to represent a mechanistic background of depression[2,3], and implying that MDD is a brain circuit disorder[3]. A recent study demonstrated that ketamine’s dissociative effects are not entirely discernible from therapeutic action and might even predict a more robust and sustained antidepressant efficacy[10]. This dual action might result from affecting the same multifunctional regions, which are involved in both effects. Facing ketamine’s complex action over time, it is important to disentangle the mechanistic network alterations underlying ketamine’s activity at different time points
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