title: 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.
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.|Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Nisha
authors.identifier: 0000-0002-1312-688X
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Sharpley
authors.affiliation: The Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Uzay E
authors.initials: UE
authors.lastname: Emir
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Masaki
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ, USA.|Palestinian Neuroscience Initiative, Faculty of Medicine, Al-Quds University, Abu Dis, Jerusalem, Palestine.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Herzallah
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gluck
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Harmer
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Sridhar R
authors.initials: SR
authors.lastname: Vasudevan
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Cowen
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004644:Emotions / Q000187:drug effects; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D054833:Isoindoles; D007858:Learning / Q000187:drug effects; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D012054:Reinforcement, Psychology; D012890:Sleep / Q000187:drug effects; D011795:Surveys and Questionnaires; D013997:Time Factors; D055815:Young Adult
chemical_list: D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D007294:Inositol; D008094:Lithium