394. THE EFFECTS OF EBSELEN ADDITION ON GLX AND GLUTAMATE LEVELS IN THE ANTERIOR CINGULATE CORTEX IN CLINICALLY DEPRESSED PATIENTS TAKING ANTIDEPRESSANT MEDICATION

Abstract Background Glutamatergic dysfunction is a potential cause of depression. Many studies reported altered levels of Glx (glutamate + glutamine) and glutamate in patients with major depressive disorder. Drugs targeting glutamatergic neurotransmission, such as ketamine, have shown rapid antidepressant effects. Interestingly, previous studies in healthy volunteers had incidentally found the ability of ebselen to reduce Glx, glutamate, and glutamine levels in the anterior cingulate cortex (ACC). A Positron Emission Tomography (PET) study using a rodent model further supported an effect of ebselen on the glutamatergic system, evidenced by reduced glutamatergic neurotransmission. Aims & Objectives The objective of the study was to investigate the effects of ebselen addition in MDD patients who were still depressed on their current antidepressant treatment on Glx and glutamate levels in the ACC. Method We conducted a double-blind, placebo-controlled, experimental medicine study to investigate the effects of ebselen addition in MDD patients who were still depressed despite current adequate dosing and duration of antidepressant treatment. Patients were randomized to receive either ebselen 600 mg twice daily or matching placebo for one week. Magnetic Resonance Spectroscopy (MRS) at 3 Tesla, Montgomery-Asberg Depression Rating Scale, and Emotional Testing Battery were conducted at baseline and on day 7 of treatment. LCModel was used to measure Glx and glutamate concentrations. Analysis of variance (ANOVA) was conducted to find any interaction between within-subject and between-sebject factors, followed by post-hoc paired t-tests if there were significant treatment interactions. Results The two-way ANOVA for Glx (F1,41 = 6.79, p = 0.013) and glutamate (F1,41 = 5.75, p = 0.021) showed significant interactions between time and treatment. A follow-up paired t-test showed a significant reduction in Glx levels in ebselen (t(23) = -3.591, p = 0.002) but not in placebo (t(18) = 1.144, p = 0.268) groups. There was a trend towards reduction in glutamate levels in the ebselen group, but the result did not reach statistical significance (t(23) = -1.982, p = 0.060). One week of ebselen treatment had no impact on the depressive symptoms of the patients and did not alter tasks of emotional processing that are sensitive to conventional antidepressant medication. Discussion & Conclusions Similar to previous studies in healthy volunteers, ebselen reduced Glx levels in the ACC. The reductions in Glx levels might be attributed to the ability of ebselen- demonstrated in preclinical studies- to inhibit glutaminase and glutamate dehydrogenase. This might explain the reduction in glutamatergic neurotransmission in the PET study cited above. The effect of ebselen on the glutamatergic system is of interest, as drugs targeting this system produce rapid antidepressant effects. Also, glutamate hyperactivity has been linked to a variety of neurological conditions including epilepsy and Alzheimer’s Disease. Future studies should involve PET work in humans to confirm that ebselen specifically decreases glutamate released as a neurotransmitter. From the viewpoint of clinical indications, a pilot study has shown that ebselen produces antimanic effects in bipolar patients and further longer-term studies of ebselen in bipolar disorder are warranted. The current data do not support the use of ebselen as an augmentation treatment in patients with treatment-resistant depression.