Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans

Abstract

Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood-brain barrier-penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm, and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder that can be tested in future clinical trials.

Figures

Figure 1

Ebselen is orally bioavailable, well tolerated, and decreases myo-inositol in the anterior cingulate cortex in humans. (a) Simplified diagram showing the central role of IMPase in the inositol cycle and its effect on several signaling pathways. PA, phosphatidic acid; PI, phosphatidylinositol; PK, protein kinase. (b) Schematic of experimental design. (c) Brain slice images from magnetic resonance imaging (MRI) showing locations of spectroscopic voxels in the anterior cingulate cortex and occipital cortex. (d) Proton magnetic resonance spectroscopy (MRS) spectrum traces illustrating the quantification of myo-inositol in the anterior cingulate cortex. A color-coded label specifies each trace. (e) Effect of ebselen on myo-inositol in the anterior cingulate cortex and the occipital cortex. (f) Correlation plots between myo-inositol and total creatine (creatine plus creatine phosphate). (g) Ebselen decreases slow-wave sleep. (h) Correlation plot between ebselen-induced changes in myo-inositol and slow-wave sleep (SWS). (i) Plasma levels of ebselen and its metabolites based on quantification of selenium. (j) Comparison of the frequency of side effects reported by participants after taking ebselen or placebo. Bar charts (e and g) show the mean±SEM (n=16) with actual p calculated by a paired two-way t-test. Scatter plots (f and h) show Pearson's correlation coefficient (r) with actual p calculated as a two-way test (n=16).

Figure 2

Ebselen affects learning influenced by either reward or punishment. (a) Schematic of experimental design. (b) Schematic of the reward and punishment learning task. The task involves picking one card at a time from four decks with two conditions, ‘pick the best deck' or ‘avoid the worst deck', and through trial and error the participant learns which of the four decks of virtual cards provides the most points in a paradigm of reward or punishment. Ebselen could increase or decrease learning relative to the placebo learning response. (c–e) Effect of ebselen on total correct choices made over time under conditions of both reward and punishment (c), as well as under the reward (d) and punishment (e) condition separately. (f) Effect of ebselen on total learning. Statistical comparisons were made with a two-way repeated measures analysis of variance with actual p shown (n=20).

Figure 3

Ebselen increases the recognition of certain emotions but not others in facial expressions. (a) Schematic of the facial emotional expression recognition task. (b) Effect of ebselen on parameters related to the ability to recognize facial emotion. (c) Effect of ebselen on the ability to correctly recognize varying degrees of facial emotional expression. All data are plotted as mean±SEM with n=20. Statistical comparisons were performed with a two-way repeated measures analysis of variance. Statistical comparisons for (c) were performed by fitting a four-parameter equation (top, bottom, half-maximum and slope) and comparing whether the data sets were better fit with a common curve or independent curves. Actual p-values are shown in the panels.

Figure 4

Ebselen decreases the latency in the emotion potentiated startle task. (a) Schematic of the startle task. An emotional image shown for 13 s modifies the latency and amplitude of an eye blink response elicited by an acoustic startle (100 dB, 100 ms). (b) Effect of ebselen on the emotionally modified startle reflex. Statistical comparisons were performed with a two-way analysis of variance with the p-values for interaction, treatment, and emotion, respectively: Z-score: 0.081, 0.72, and 0.009; amplitude: 0.79, 0.51, and 0.011; and latency: 0.44, 0.01, and 0.77. Each graph is labeled with the most salient p-value for its parameter.