title: Lithium and Valproate Levels Do Not Correlate with Ketamine's Antidepressant Efficacy in Treatment-Resistant Bipolar Depression.
abstract: Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine's antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine's antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar depression maintained on therapeutic-dose lithium (n = 23, 0.79 ± 0.15 mEq/L) or valproate (n = 13, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary depression outcome measure-the Montgomery-Åsberg Depression Rating Scale (MADRS)-was assessed before infusion and at numerous postinfusion time points. Both lithium (F 1,118 = 152.08, p < 0.001, and d = 2.27) and valproate (F 1,128 = 20.12, p < 0.001, and d = 0.79) significantly improved depressive symptoms, but no statistically significant difference was observed between mood stabilizer groups (F 1,28 = 2.51, p = 0.12, and d = 0.60). Serum lithium and valproate levels did not correlate with ketamine's antidepressant efficacy. Although the study was potentially underpowered, our results suggest that lithium may not potentiate ketamine's antidepressant efficacy in treatment-resistant bipolar depression.
authors.affiliation: New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595, USA.
authors.forename: Annie J
authors.initials: AJ
authors.lastname: Xu
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Niciu
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Lundin
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.affiliation: Massachusetts General Hospital, Depression Clinical & Research Program, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, USA.
authors.forename: Dawn F
authors.initials: DF
authors.lastname: Ionescu
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Richards
authors.affiliation: Department of Psychiatry & Psychological Services, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Vande Voort
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Ballard
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Brutsche
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy*; D018592:Cross-Over Studies; D061218:Depressive Disorder, Treatment-Resistant / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D008094:Lithium / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D014635:Valproic Acid / Q000097:blood*
chemical_list: D000928:Antidepressive Agents; D014635:Valproic Acid; D007649:Ketamine; D008094:Lithium